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Metabolic alkalosis is a widespread acid-base disturbance, especially in hospitalized patients. It is characterized by the primary elevation of serum bicarbonate and arterial pH, along with a compensatory increase in Pco2 consequent to adaptive hypoventilation. The pathogenesis of metabolic alkalosis involves either a loss of fixed acid or a net accumulation of bicarbonate within the extracellular fluid. The loss of acid may be via the gastrointestinal tract or the kidney, whereas the sources of excess alkali may be via oral or parenteral alkali intake. Severe metabolic alkalosis in critically ill patients-arterial blood pH of 7.55 or higher-is associated with significantly increased mortality rate. The kidney is equipped with sophisticated mechanisms to avert the generation or the persistence (maintenance) of metabolic alkalosis by enhancing bicarbonate excretion. These mechanisms include increased filtration as well as decreased absorption and enhanced secretion of bicarbonate by specialized transporters in specific nephron segments. Factors that interfere with these mechanisms will impair the ability of the kidney to eliminate excess bicarbonate, therefore promoting the generation or impairing the correction of metabolic alkalosis. These factors include volume contraction, low glomerular filtration rate, potassium deficiency, hypochloremia, aldosterone excess, and elevated arterial carbon dioxide. Major clinical states are associated with metabolic alkalosis, including vomiting, aldosterone or cortisol excess, licorice ingestion, chloruretic diuretics, excess calcium alkali ingestion, and genetic diseases such as Bartter syndrome, Gitelman syndrome, and cystic fibrosis. In this installment in the AJKD Core Curriculum in Nephrology, we will review the pathogenesis of metabolic alkalosis; appraise the precipitating events; and discuss clinical presentations, diagnoses, and treatments of metabolic alkalosis.
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Alcalosis , Bicarbonatos , Aldosterona , Álcalis , Alcalosis/diagnóstico , Alcalosis/etiología , Alcalosis/terapia , Bicarbonatos/metabolismo , Bicarbonatos/uso terapéutico , Calcio , Dióxido de Carbono , Curriculum , Diuréticos , Humanos , HidrocortisonaRESUMEN
[This corrects the article DOI: 10.1371/journal.pgen.1007785.].
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Dozens of millions of people are exposed to gadolinium-based contrast agents annually for enhanced magnetic resonance imaging. Gadolinium-based contrast agents are known nephrotoxins and can trigger the potentially fatal condition of systemic fibrosis. Risk factors are practically entirely undefined. We examined the role of NADPH oxidase 4 (Nox4) in gadolinium-induced systemic disease. Age- and weight-matched mice were randomized to experimental diabetes (streptozotocin) and control groups followed by systemic gadolinium-based contrast agent treatment. Nox4-deficient mice were randomized to experimental diabetes and gadolinium-based contrast agent treatment. Skin fibrosis and cellular infiltration were apparent in both gadolinium-based contrast agent-treated and experimental diabetes groups. Similarly, both groups demonstrated renal pathologies with evidence of reactive oxygen species generation. Deletion of Nox4 abrogated both skin and renal pathology, whether from diabetes or gadolinium-based contrast agent treatment. These discoveries demonstrate the importance of Nox4 in gadolinium-based contrast agent- and diabetes-induced fibrosis.NEW & NOTEWORTHY A mouse model of gadolinium-based contrast agent- and diabetes-induced fibrosis was used to demonstrate the role of NADPH oxidase 4 (Nox4) in gadolinium-induced systemic disease. Using these models, we established the role of Nox4 as a mediator of reactive oxygen species generation and subsequent skin and kidney fibrosis. These novel findings have defined Nox-4-mediated mechanisms by which gadolinium-based contrast agents induce systemic diseases.
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Medios de Contraste/efectos adversos , Fibrosis/inducido químicamente , Gadolinio/efectos adversos , NADPH Oxidasa 4/efectos de los fármacos , Insuficiencia Renal/patología , Animales , Diabetes Mellitus Experimental/inducido químicamente , Fibrosis/patología , Riñón/efectos de los fármacos , Riñón/patología , Enfermedades Renales/inducido químicamente , Enfermedades Renales/patología , Ratones , NADPH Oxidasa 4/metabolismo , Dermopatía Fibrosante Nefrogénica/inducido químicamente , Dermopatía Fibrosante Nefrogénica/patología , Insuficiencia Renal/inducido químicamenteRESUMEN
SUMMARY: Methods for quantifying the imbalance in CpG methylation between alleles genome-wide have been described but their algorithmic time complexity is quadratic and their practical use requires painstaking attention to infrastructure choice, implementation and execution. To solve this problem, we developed CloudASM, a scalable, ultra-efficient, turn-key, portable pipeline on Google Cloud Platform (GCP) that uses a novel pipeline manager and GCP's serverless enterprise data warehouse. AVAILABILITY AND IMPLEMENTATION: CloudASM is freely available in the GitHub repository https://github.com/TyckoLab/CloudASM and a sample dataset and its results are also freely available at https://console.cloud.google.com/storage/browser/cloudasm. CONTACT: emmanuel.dumont@hmh-cdi.org.
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Metilación de ADN , Programas Informáticos , Alelos , Nube ComputacionalRESUMEN
From genomic association studies, quantitative trait loci analysis, and epigenomic mapping, it is evident that significant efforts are necessary to define genetic-epigenetic interactions and understand their role in disease susceptibility and progression. For this reason, an analysis of the effects of genetic variation on gene expression and DNA methylation in human placentas at high resolution and whole-genome coverage will have multiple mechanistic and practical implications. By producing and analyzing DNA sequence variation (n = 303), DNA methylation (n = 303) and mRNA expression data (n = 80) from placentas from healthy women, we investigate the regulatory landscape of the human placenta and offer analytical approaches to integrate different types of genomic data and address some potential limitations of current platforms. We distinguish two profiles of interaction between expression and DNA methylation, revealing linear or bimodal effects, reflecting differences in genomic context, transcription factor recruitment, and possibly cell subpopulations. These findings help to clarify the interactions of genetic, epigenetic, and transcriptional regulatory mechanisms in normal human placentas. They also provide strong evidence for genotype-driven modifications of transcription and DNA methylation in normal placentas. In addition to these mechanistic implications, the data and analytical methods presented here will improve the interpretability of genome-wide and epigenome-wide association studies for human traits and diseases that involve placental functions.
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Variación Genética , Placenta/metabolismo , Adolescente , Adulto , Sitios de Unión/genética , Islas de CpG , Metilación de ADN/genética , Epigénesis Genética , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Genoma Humano , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Polimorfismo de Nucleótido Simple , Embarazo , Sitios de Carácter Cuantitativo , Análisis de Secuencia de ADN , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Adulto JovenRESUMEN
Haplotype-dependent allele-specific methylation (hap-ASM) can impact disease susceptibility, but maps of this phenomenon using stringent criteria in disease-relevant tissues remain sparse. Here we apply array-based and Methyl-Seq approaches to multiple human tissues and cell types, including brain, purified neurons and glia, T lymphocytes, and placenta, and identify 795 hap-ASM differentially methylated regions (DMRs) and 3,082 strong methylation quantitative trait loci (mQTLs), most not previously reported. More than half of these DMRs have cell type-restricted ASM, and among them are 188 hap-ASM DMRs and 933 mQTLs located near GWAS signals for immune and neurological disorders. Targeted bis-seq confirmed hap-ASM in 12/13 loci tested, including CCDC155, CD69, FRMD1, IRF1, KBTBD11, and S100A(∗)-ILF2, associated with immune phenotypes, MYT1L, PTPRN2, CMTM8 and CELF2, associated with neurological disorders, NGFR and HLA-DRB6, associated with both immunological and brain disorders, and ZFP57, a trans-acting regulator of genomic imprinting. Polymorphic CTCF and transcription factor (TF) binding sites were over-represented among hap-ASM DMRs and mQTLs, and analysis of the human data, supplemented by cross-species comparisons to macaques, indicated that CTCF and TF binding likelihood predicts the strength and direction of the allelic methylation asymmetry. These results show that hap-ASM is highly tissue specific; an important trans-acting regulator of genomic imprinting is regulated by this phenomenon; and variation in CTCF and TF binding sites is an underlying mechanism, and maps of hap-ASM and mQTLs reveal regulatory sequences underlying supra- and sub-threshold GWAS peaks in immunological and neurological disorders.
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Metilación de ADN , Impresión Genómica , Haplotipos/genética , Polimorfismo de Nucleótido Simple/genética , Sitios de Carácter Cuantitativo , Transactivadores/genética , Alelos , Animales , Encéfalo/metabolismo , Encéfalo/patología , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Enfermedades del Sistema Inmune/genética , Macaca mulatta , Macaca radiata , Enfermedades del Sistema Nervioso/genética , Placenta/metabolismo , Placenta/patología , Embarazo , Especificidad de la Especie , Linfocitos T/metabolismo , Linfocitos T/patologíaRESUMEN
Evidence for gadolinium-based contrast agent- (GBCA-) induced disease continues to mount. Risk factors for gadolinium-induced systemic fibrosis are entirely unexplored. Obesity-related renal injury is characterized by activation of glomerular mesangial cells and podocyte damage with alteration of lipid metabolism/lipid accumulation in both cell types resulting in matrix accumulation and eventual progression to glomerulosclerosis. We examined the consequences of GBCA treatment in the kidneys from mice with normal kidney function and the potential interplay between obesity and gadolinium exposure. We found that administration of GBCA (4â¯weeks) causes significant renal fibrosis and podocyte injury that are associated with metabolic disorders as evidenced by dyslipidemia. Metabolomic analysis demonstrated that renal lipid metabolism and metabolic markers of collagen turnover are significantly altered by gadolinium. GBCA stimulates myeloid-derived fibrocytes to the kidney. Obesity was induced by feeding a group of mice a high fat diet (HFD) for 22â¯weeks. Groups were sub-randomized to GBCA treatment versus none for 4â¯weeks before sacrifice. HFD-induced fibrosis and podocyte injury were worsened by GBCA. Similarly, HFD-mediated hyperlipidemia and lipid metabolites were exacerbated by gadolinium. This is the first evidence that GBCA causes significant metabolic disorders and kidney injury in mice without renal insufficiency and that the injurious actions of GBCA are amplified by obesity. The understanding of the functional interplay between gadolinium and obesity will allow the development of therapeutic interventions or the establishment of effective preventive measures to reduce gadolinium- and obesity-mediated renal pathologies.
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Medios de Contraste/efectos adversos , Gadolinio/efectos adversos , Enfermedades Renales/inducido químicamente , Animales , Trasplante de Médula Ósea , Dieta Alta en Grasa , Femenino , Fibrosis , Riñón/patología , Ratones , Ratones Endogámicos C57BL , Nefrectomía , Distribución AleatoriaRESUMEN
OBJECTIVE: The purpose of this study was to assess risk of progression and rate of growth of presumed low-risk branch duct intraductal papillary mucinous neoplasms surveyed for more than 4 years. MATERIALS AND METHODS: A keyword search of electronic medical charts was performed for the years 2001-2013. Cystic lesions that met the criteria for clinical branch duct intraductal papillary mucinous neoplasm, lacked baseline high-risk or worrisome features, and had more than 4 years of surveillance were included in this study. Two radiologists performed cyst size measurements to assess interreader variability. Cyst progression was defined either as 2-mm or greater or 20% or greater increase in diameter or as development of worrisome features. Kaplan-Meier curves were generated to evaluate cyst progression time and linear mixed models to evaluate growth rates. RESULTS: The search revealed 2423 patients with cystic pancreatic lesions. Among these patients 228 had imaging follow-up for 4 or more years, and 131 met the clinical criteria for branch duct intraductal papillary mucinous neoplasms. Among the 131 cysts, 73 (55.7%) progressed: 61 (46.6%) increased in size, 10 (7.6%) increased in size and developed worrisome features, and two (1.5%) developed worrisome features only. Of the 71 cysts that increased in size, 50 (70.4%) did so within the first 5 years, and 21 (29.6%) grew after 5 years. No patient had adenocarcinoma. There was no significant difference in growth rate based on cyst size within the first 50 months. After 50 months, cysts larger than 20 mm continued to increase in size (p < 0.05) and had faster growth rates. CONCLUSION: Among presumed low-risk branch duct intraductal papillary mucinous neoplasms, most increased in size, approximately 30% after 5 years. Cysts with baseline size larger than 20 mm continued to grow beyond 5 years at a faster rate.
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Adenocarcinoma Mucinoso/diagnóstico por imagen , Adenocarcinoma Mucinoso/patología , Carcinoma Ductal Pancreático/diagnóstico por imagen , Carcinoma Ductal Pancreático/patología , Carcinoma Papilar/diagnóstico por imagen , Carcinoma Papilar/patología , Imagen por Resonancia Magnética/métodos , Quiste Pancreático/diagnóstico por imagen , Quiste Pancreático/patología , Neoplasias Pancreáticas/diagnóstico por imagen , Neoplasias Pancreáticas/patología , Anciano , Pancreatocolangiografía por Resonancia Magnética , Progresión de la Enfermedad , Femenino , Humanos , Interpretación de Imagen Asistida por Computador , Imagenología Tridimensional , Masculino , Persona de Mediana Edad , Vigilancia de la Población , Estudios RetrospectivosRESUMEN
Plasmablastic lymphoma is a rare and aggressive diffuse large B-cell lymphoma commonly associated with Epstein-Barr virus co-infection that most often occurs in the context of human immunodeficiency virus infection. Therefore, its immune escape strategy may involve the upregulation of immune-checkpoint proteins allowing the tumor immune evasion. However, the expression of these molecules was poorly studied in this lymphoma. We have investigated 82 plasmablastic lymphoma cases of whom half were Epstein-Barr virus positive. Although they harbored similar pathological features, Epstein-Barr virus positive plasmablastic lymphomas showed a significant increase in MYC gene rearrangement and had a better 2-year event-free survival than Epstein-Barr virus negative cases (P=0.049). Immunostains for programmed cell death-1, programmed cell death-ligand 1, indole 2,3-dioxygenase and dendritic cell specific C-type lectin showed a high or moderate expression by the microenvironment cells in 60%-72% of cases, whereas CD163 was expressed in almost all cases. Tumor cells also expressed programmed cell death-1 and its ligand in 22.5% and 5% of cases, respectively. Both Epstein-Barr virus positive and negative plasmablastic lymphomas exhibited a high immune-checkpoint score showing that it involves several pathways of immune escape. However, Epstein-Barr virus positive lymphomas exhibited a higher expression of programmed cell death-1 and its ligand in both malignant cells and microenvironment as compared to Epstein-Barr virus negative cases. In conclusion, plasmablastic lymphoma expresses immune-checkpoint proteins through both malignant cells and the tumor microenvironment. The expression of programmed cell death-1 and its ligand constitutes a strong rationale for testing monoclonal antibodies in this often chemoresistant disease.
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Biomarcadores de Tumor , Infecciones por Virus de Epstein-Barr/complicaciones , Expresión Génica , Herpesvirus Humano 4/genética , Inmunomodulación/genética , Linfoma Plasmablástico/diagnóstico , Linfoma Plasmablástico/etiología , Adulto , Anciano , Biopsia , Terapia Combinada , Femenino , Estudios de Asociación Genética , Humanos , Inmunohistoquímica , Inmunofenotipificación , Hibridación Fluorescente in Situ , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Fenotipo , Linfoma Plasmablástico/mortalidad , Linfoma Plasmablástico/terapia , Pronóstico , Translocación Genética , Resultado del TratamientoRESUMEN
Allele-specific DNA methylation (ASM) is well studied in imprinted domains, but this type of epigenetic asymmetry is actually found more commonly at non-imprinted loci, where the ASM is dictated not by parent-of-origin but instead by the local haplotype. We identified loci with strong ASM in human tissues from methylation-sensitive SNP array data. Two index regions (bisulfite PCR amplicons), one between the C3orf27 and RPN1 genes in chromosome band 3q21 and the other near the VTRNA2-1 vault RNA in band 5q31, proved to be new examples of imprinted DMRs (maternal alleles methylated) while a third, between STEAP3 and C2orf76 in chromosome band 2q14, showed non-imprinted haplotype-dependent ASM. Using long-read bisulfite sequencing (bis-seq) in 8 human tissues we found that in all 3 domains the ASM is restricted to single differentially methylated regions (DMRs), each less than 2kb. The ASM in the C3orf27-RPN1 intergenic region was placenta-specific and associated with allele-specific expression of a long non-coding RNA. Strikingly, the discrete DMRs in all 3 regions overlap with binding sites for the insulator protein CTCF, which we found selectively bound to the unmethylated allele of the STEAP3-C2orf76 DMR. Methylation mapping in two additional genes with non-imprinted haplotype-dependent ASM, ELK3 and CYP2A7, showed that the CYP2A7 DMR also overlaps a CTCF site. Thus, two features of imprinted domains, highly localized DMRs and allele-specific insulator occupancy by CTCF, can also be found in chromosomal domains with non-imprinted ASM. Arguing for biological importance, our analysis of published whole genome bis-seq data from hES cells revealed multiple genome-wide association study (GWAS) peaks near CTCF binding sites with ASM.
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Alelos , Proteínas Sanguíneas/genética , Metilación de ADN/genética , Proteínas Fetales/genética , Estudio de Asociación del Genoma Completo , Impresión Genómica , Proteínas Oncogénicas/genética , Hidrocarburo de Aril Hidroxilasas/genética , Factor de Unión a CCCTC , Cromosomas/genética , Familia 2 del Citocromo P450 , Haplotipos , Humanos , Polimorfismo de Nucleótido Simple , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas c-ets , ARN Largo no Codificante/genética , Proteínas Represoras/genética , Sensibilidad y Especificidad , Factores de Transcripción/genéticaRESUMEN
It has been presupposed that the thermodynamic stability constant (K(therm)) of gadolinium-based MRI chelates relate to the risk of precipitating nephrogenic systemic fibrosis. The present study compared low-K(therm) gadodiamide with high-K(therm) gadoteridol in cultured fibroblasts and rats with uninephrectomies. Gadolinium content was assessed using scanning electron microscopy equipped with energy-dispersive X-ray spectroscopy in paraffin-embedded tissues. In vitro, fibroblasts demonstrated dose-dependent fibronectin generation, transforming growth factor-ß production, and expression of activated myofibroblast stress fiber protein α-smooth muscle actin. There were negligible differences with respect to toxicity or proliferation between the two contrast agents. In the rodent model, gadodiamide treatment led to greater skin fibrosis and dermal cellularity than gadoteridol. In the kidney, both contrast agents led to proximal tubule vacuolization and increased fibronectin accumulation. Despite large detectable gadolinium signals in the spleen, skin, muscle, and liver from the gadodiamide-treated group, contrast-induced fibrosis appeared to be limited to the skin and kidney. These findings support the hypothesis that low-K(therm) chelates have a greater propensity to elicit nephrogenic systemic fibrosis and demonstrate that certain tissues are resistant to these effects.
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Medios de Contraste/efectos adversos , Gadolinio DTPA/efectos adversos , Compuestos Heterocíclicos/efectos adversos , Dermopatía Fibrosante Nefrogénica/inducido químicamente , Compuestos Organometálicos/efectos adversos , Animales , Células Cultivadas , Medios de Contraste/química , Femenino , Fibroblastos/metabolismo , Fibronectinas/metabolismo , Gadolinio/efectos adversos , Gadolinio/química , Gadolinio DTPA/química , Compuestos Heterocíclicos/química , Humanos , Imagen por Resonancia Magnética , Dermopatía Fibrosante Nefrogénica/metabolismo , Compuestos Organometálicos/química , Ratas Endogámicas F344 , Insuficiencia Renal/complicaciones , TermodinámicaRESUMEN
PCDH10 is epigenetically inactivated in multiple tumor types; however, studies in mature lymphoid malignancies are limited. Here, we have investigated the presence of promoter hypermethylation of the PCDH10 gene in a large cohort of well-characterized subsets of lymphomas. PCDH10 promoter hypermethylation was identified by methylation-specific PCR in 57 to 100% of both primary B- and T-cell lymphoma specimens and cell lines. These findings were further validated by Sequenom Mass-array analysis. Promoter hypermethylation was also identified in 28.6% cases of reactive follicular hyperplasia, more commonly occurring in states of immune deregulation and associated with rare presence of clonal karyotypic aberrations, suggesting that PCDH10 methylation occurs early in lymphomagenesis. PCDH10 expression was down regulated via promoter hypermethylation in T- and B-cell lymphoma cell lines. The transcriptional down-regulation resulting from PCDH10 methylation could be restored by pharmacologic inhibition of DNA methyltransferases in cell lines. Both T- and B-cell lymphoma cell lines harboring methylation-mediated inactivation of PCDH10 were resistant to doxorubicin treatment, suggesting that hypermethylation of this gene might contribute to chemotherapy response.
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Antibióticos Antineoplásicos/farmacología , Cadherinas/genética , Metilación de ADN , Doxorrubicina/farmacología , Linfoma no Hodgkin/genética , Mieloma Múltiple/genética , Regiones Promotoras Genéticas , Apoptosis/efectos de los fármacos , Carcinogénesis/genética , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Metilasas de Modificación del ADN/antagonistas & inhibidores , Regulación hacia Abajo/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Cariotipo , Linfoma no Hodgkin/patología , Mieloma Múltiple/patología , Protocadherinas , Espectrometría de Masa por Láser de Matriz Asistida de Ionización DesorciónRESUMEN
A number of factors contribute to cell type-specific CTCF chromatin binding, but how they act in concert to determine binding stability and functionality has not been fully elucidated. In this review, we tie together different layers of regulation to provide a holistic view of what is known. What emerges from these studies is a multifaceted system in which DNA sequence, DNA and chromatin accessibility, and cell type-specific transcription factors together contribute to CTCF binding profile and function. We discuss these findings in the light of disease settings in which changes in the chromatin landscape and transcriptional programming can disrupt CTCF's binding profile and involvement in looping.
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Aberrations in the capacity of DNA/chromatin modifiers and transcription factors to bind non-coding regions can lead to changes in gene regulation and impact disease phenotypes. However, identifying distal regulatory elements and connecting them with their target genes remains challenging. Here, we present MethNet, a pipeline that integrates large-scale DNA methylation and gene expression data across multiple cancers, to uncover cis regulatory elements (CREs) in a 1 Mb region around every promoter in the genome. MethNet identifies clusters of highly ranked CREs, referred to as 'hubs', which contribute to the regulation of multiple genes and significantly affect patient survival. Promoter-capture Hi-C confirmed that highly ranked associations involve physical interactions between CREs and their gene targets, and CRISPR interference based single-cell RNA Perturb-seq validated the functional impact of CREs. Thus, MethNet-identified CREs represent a valuable resource for unraveling complex mechanisms underlying gene expression, and for prioritizing the verification of predicted non-coding disease hotspots.
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Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Neoplasias , Regiones Promotoras Genéticas , Humanos , Neoplasias/genética , Metilación de ADN/genética , Regiones Promotoras Genéticas/genética , Secuencias Reguladoras de Ácidos Nucleicos/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
The phenotype of human placental extravillous trophoblast (EVT) at the end of pregnancy reflects both first trimester differentiation from villous cytotrophoblast (CTB) and later gestational changes, including loss of proliferative and invasive capacity. Invasion abnormalities are central to two major placental pathologies, preeclampsia and placenta accreta spectrum, so characterization of the corresponding normal processes is crucial. In this report, our gene expression analysis, using purified human CTB and EVT cells, highlights an epithelial-mesenchymal transition (EMT) mechanism underlying CTB-EVT differentiation and provides a trophoblast-specific EMT signature. In parallel, DNA methylation profiling shows that CTB cells, already hypomethylated relative to non-trophoblast cell lineages, show further genome-wide hypomethylation in the transition to EVT. However, a small subgroup of genes undergoes gains of methylation (GOM) in their regulatory regions or gene bodies, associated with differential mRNA expression (DE). Prominent in this GOM-DE group are genes involved in the EMT, including multiple canonical EMT markers and the EMT-linked transcription factor RUNX1, for which we demonstrate a functional role in modulating the migratory and invasive capacities of JEG3 trophoblast cells. This analysis of DE associated with locus-specific GOM, together with functional studies of an important GOM-DE gene, highlights epigenetically regulated genes and pathways acting in human EVT differentiation and invasion, with implications for obstetric disorders in which these processes are dysregulated.
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Background: Non-melanoma skin cancer (NMSC) is the most prevalent cancer in the United States. Despite guidelines on ultraviolet (UV) avoidance, it remains difficult for people to assess their exposure, as UV is invisible and the onset of UV-induced symptoms is delayed. Methods: In a prospective randomized trial, 97 elderly patients with a history of actinic keratoses (AK) were followed over 6 months. Fifty patients received UV counseling from a dermatologist and a wearable UV dosimeter that provided real-time and cumulative UV exposure. Forty-seven patients received only UV counseling from a dermatologist. Results: Over 75% of participants recorded UV exposure at least once a week during the summer. After 6 months of intervention, when comparing the device group to the control group, we observed a non-significant 20% lower ratio of incidence rates of AKs (95% CI = [-41, 55%], p-value = 0.44) and a significant 95% lower ratio of incidence rates of NMSCs (95% CI = [33, 99.6%], p-value = 0.024). Surveys demonstrated that the control group's score in self-perceived ability to participate in social activities significantly increased by 1.2 (p-value = 0.04), while in the device group, this score non-significantly decreased by 0.9 (p-value = 0.1). We did not observe changes, or between-group differences, in anxiety and depression surveys. Conclusion: This pilot clinical trial has a short duration and a small sample size. However, device adherence and quality of life questionnaires suggest a smartphone-connected wearable UV dosimeter is well accepted by an elderly population. This trial also indicates that a wearable UV dosimeter may be an effective behavioral change tool to reduce NMSC incidence in an elderly population with a prior history of AKs.Clinical trial registration: clinicaltrials.gov, identifier NCT03315286.
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Although only a fraction of CTCF motifs are bound in any cell type, and approximately half of the occupied sites overlap cohesin, the mechanisms underlying cell-type specific attachment and ability to function as a chromatin organizer remain unknown. To investigate the relationship between CTCF and chromatin we applied a combination of imaging, structural and molecular approaches, using a series of brain and cancer associated CTCF mutations that act as CTCF perturbations. We demonstrate that binding and the functional impact of WT and mutant CTCF depend not only on the unique properties of each protein, but also on the genomic context of bound sites. Our studies also highlight the reciprocal relationship between CTCF and chromatin, demonstrating that the unique binding properties of WT and mutant proteins have a distinct impact on accessibility, TF binding, cohesin overlap, chromatin interactivity and gene expression programs, providing insight into their cancer and brain related effects.
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Although only a fraction of CTCF motifs are bound in any cell type, and approximately half of the occupied sites overlap cohesin, the mechanisms underlying cell-type specific attachment and ability to function as a chromatin organizer remain unknown. To investigate the relationship between CTCF and chromatin we applied a combination of imaging, structural and molecular approaches, using a series of brain and cancer associated CTCF mutations that act as CTCF perturbations. We demonstrate that binding and the functional impact of WT and mutant CTCF depend not only on the unique properties of each protein, but also on the genomic context of bound sites. Our studies also highlight the reciprocal relationship between CTCF and chromatin, demonstrating that the unique binding properties of WT and mutant proteins have a distinct impact on accessibility, TF binding, cohesin overlap, chromatin interactivity and gene expression programs, providing insight into their cancer and brain related effects.
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CD8+ CTLs are thought to play a role in the control of follicular lymphoma (FL). Yet, the link between CTL tissue distribution, activation status, ability to kill FL cells in vivo, and disease progression is still elusive. Pretreatment lymph nodes from FL patients were analyzed by IHC (n = 80) or by 3-color confocal microscopy (n = 10). IHC revealed a rich infiltrate of CD8+ granzyme B+ (GrzB) cells in FL interfollicular spaces. Accordingly, confocal microscopy showed an increased number of CD3+CD8+GrzB+ CTLs and a brighter GrzB staining in individual CTL in FL samples compared with reactive lymph nodes. CTLs did not penetrate tumor nodules. In 3-dimensional (3-D) image reconstructions, CTLs were detected at the FL follicle border where they formed lytic synapse-like structures with FL B cells and with apoptotic cells, suggesting an in situ cytotoxic function. Finally, although GrzB expression in CTLs did not correlate with risk factors, high GrzB content correlated with prolonged progression free-survival (PFS) after rituximab-combined chemotherapy. Our results show the recruitment of armed CTLs with a tumor-controlling potential into FL lymph nodes and suggest that CTL-associated GrzB expression could influence PFS in FL patients having received rituximab-combined chemotherapy.
Asunto(s)
Imagenología Tridimensional , Ganglios Linfáticos/patología , Linfoma Folicular/epidemiología , Linfoma Folicular/patología , Linfocitos T Citotóxicos/patología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Biomarcadores de Tumor/metabolismo , Complejo CD3/metabolismo , Antígenos CD8/metabolismo , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Granzimas/metabolismo , Humanos , Linfoma Folicular/tratamiento farmacológico , Masculino , Microscopía Confocal/métodos , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Prednisona/administración & dosificación , Pronóstico , Factores de Riesgo , Rituximab , Linfocitos T Citotóxicos/metabolismo , Vincristina/administración & dosificaciónRESUMEN
BACKGROUND: In contrast to sessile serrated adenomas and traditional serrated adenomas which are associated with a significant cancer risk, the role of hyperplastic polyps (HP) in colorectal carcinogenesis as well as the molecular mechanisms underlying their development remain controversial and still need to be clarified. Several reports suggest that a subset of HP may represent precursor lesions of some colorectal cancers. However, biomarkers are needed to identify the subset of HP that may have a malignant potential. The hormone precursor, progastrin (PG) has been involved in colon carcinogenesis and is known to activate pro-oncogenic pathways such as the ERK or the STAT3 pathway. We therefore analyzed PG expression and the activation of these signaling factors in HP. METHODS: We retrospectively analyzed PG expression as well as the phosphorylation of ERK and STAT3 by immunohistochemistry in HP from 48 patients. RESULTS: Mean percentages of epithelial cells positive for PG or phospho-ERK were respectively, 31% and 33% in HP and were significantly higher in these lesions compared to normal colon (3%, p=0.0021 and 7%, p=0.0008, respectively). We found a significant correlation between PG and phospho-ERK expression in HP with ERK activation significantly stronger in lesions with high progastrin expression (p=0.015). In contrast, STAT3 was not significantly activated in HP compared to normal colon and we did not observe a significant correlation with PG expression. CONCLUSIONS: HP overexpressing PG that have the highest activation of the ERK pathway might reflect less latent lesions that might have a malignant potential.