ABSTRACT
Common variants of the MC1R gene coding the α-melanocyte stimulating hormone receptor are associated with light skin, poor tanning, blond or red hair, and increased melanoma risk, due to pigment-dependent and -independent effects. This complex phenotype is usually attributed to impaired activation of cAMP signaling. However, several MC1R variants show significant residual coupling to cAMP and efficiently activate mitogenic extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling. Yet, residual signaling and the key actions of wildtype and variant MC1R have never been assessed under strictly comparable conditions in melanocytic cells of identical genetic background. We devised a strategy based on CRISPR-Cas9 knockout of endogenous MC1R in a human melanoma cell line wildtype for BRAF, NRAS and NF1, followed by reconstitution with epitope-labeled MC1R constructs, and functional analysis of clones expressing comparable levels of wildtype, R151C or D294H MC1R. The proliferation rate, shape, adhesion, motility and sensitivity to oxidative DNA damage were compared. The R151C and D294H RHC variants displayed impaired cAMP signaling, intracellular stability similar to the wildtype, triggered ERK1/2 activation as effectively as the wildtype, and afforded partial protection against oxidative DNA damage, although less efficiently than the wildtype. Therefore, common melanoma-associated MC1R variants display biased signaling and significant genoprotective activity.
Subject(s)
Melanoma , Receptor, Melanocortin, Type 1 , Humans , Cyclic AMP/metabolism , DNA/metabolism , Melanoma/genetics , Melanoma/metabolism , Oxidative Stress , Receptor, Melanocortin, Type 1/genetics , Receptor, Melanocortin, Type 1/metabolismABSTRACT
BACKGROUND: It has been established a strong association between the red cell distribution width (RDW) and mean platelet volume (MPV) with hypertension in non-pregnant patients. However, few studies have been performed in patients with preeclampsia, yielding inconsistent results. Our aim is to evaluate the relationship between RDW and MPV with the severity of preeclampsia. METHODS: Analytic cross-sectional study. We include 64 patients with preeclampsia (26 mild, 38 severe) and 70 patients with normotensive pregnancy. Clinical data, sociodemographic characteristics and laboratory measures, including RDW and MPV, were recorded for each patient. RESULTS: Hemoglobin and platelet count measures were similar between groups. Preeclamptic patients had levels of RDW (14.7 ± 1.4 vs. 13.4 ± 0.7, p = 0.0001) and MPV (11.8 ± 2.4 vs. 11.0 ± 1.4, p = 0.03) more elevated than control group. Moreover, severe preeclamptic subgroup had more elevated levels of RDW (15.0 ± 1.6 vs. 14.0 ± 0.6, p = 0.001) and MPV (12.7 ± 2.8 vs. 10.8 ± 1.8, p = 0.01) in comparison with mild preeclamptic patients. CONCLUSIONS: We demonstrate that RDW and MPV are accessible and inexpensive measures associated with the severity of preeclampsia.
Introducción: se ha establecido fuertemente la asociación entre el ancho de distribución eritrocitario (ADE) y el volumen plaquetario medio (VPM) con la hipertensión arterial sistémica. Sin embargo, se han realizado pocos estudios en pacientes con preeclampsia, obteniéndose resultados inconsistentes. Nuestro objetivo es evaluar la relación entre el ADE y el VPM con la severidad de la preeclampsia. Métodos: incluimos 64 pacientes con preeclampsia (26 leve, 38 severa) y 70 pacientes con embarazo normotenso. Los datos clínicos, características sociodemográficas y valores de laboratorio, incluyendo ADE y VPM, fueron registrados en cada paciente. Resultados: las medidas de hemoglobina y conteo plaquetario fueron similares entre ambos grupos. Las pacientes con preeclampsia tuvieron niveles de ADE (14.7 ± 1.4 frente a 13.4 ± 0.7, p = 0.0001) y VPM (11.8 ± 2.4 frente a 11.0 ± 1.4, p = 0.03) más elevados que el grupo control. El subgrupo de preeclampsia severa tuvo niveles más elevados de ADE (15.0 ± 1.6 frente a 14.0 ± 0.6, p = 0.001) y VPM (12.7 ± 2.8 frente a 10.8 ± 1.8, p = 0.01) que las pacientes con preeclampsia leve. Conclusiones: se demuestra que el ADE y el VPM son medidas accesibles asociadas a la severidad de la preeclampsia.
Subject(s)
Erythrocyte Indices , Mean Platelet Volume , Pre-Eclampsia/blood , Pre-Eclampsia/diagnosis , Severity of Illness Index , Adult , Case-Control Studies , Cross-Sectional Studies , Female , Humans , PregnancyABSTRACT
Para abordar el problema de las anomalías congénitas en nuestra provincia es necesario delimitar su magnitud, ya que las mismas constituyen una de las principales causas de morbimortalidad neonatal, tanto por su elevada frecuencia como por las repercusiones estéticas, funcionales, psicológicas y sociales que implican. El presente estudio se llevó a cabo teniendo como objetivo determinar los factores maternos de riesgo prenatales: demográficos, pregestacionales, gestacionales que se presentaban entre los antecedentes de los recién nacidos portadores de anomalías congénitas, durante el período 2002-2005, en el Hospital Regional Dr. Ramón Carrillo de Santiago del Estero. Se realizó un estudio descriptivo, modalidad observacional, retrospectivo y de corte transversal, en una muestra de 150 casos, obtenida de una población de 285 recién nacidos con defectos congénitos. Los datos se recolectaron de la Historia Clínica Perinatal CLAP/OMS y se utilizaron como análisis estadístico, distribución de frecuencias absolutas y relativas con tablas y gráficos del programa SPSS. Los resultados determinaron un perfil materno reiterado y como se distribuían las malformaciones más frecuentemente observadas en el momento del nacimiento, según las variables analizadas que emergieron del marco teórico en cuestión. Como conclusión, quedo fijada la necesidad de continuar profundizando los estudios de esta patología e implementar en lo posible, una correcta vigilancia epidemiológica que permita la detección precoz de las mismas con una adecuada calidad de atención de la embarazada y el parto, para poder brindar un asesoramiento genético pertinente y oportuno a este grupo vulnerable de nuestra población.
To address the problem of congenital anomalies in our province is necessary to determine its magnitude, since they are a major cause of neonatal morbidity and mortality, both for its high frequency as the impact aesthetic, functional, psychological and social implications. This study was conducted aiming at identifying risk factors, maternal prenatal: demographic, pregestational, gestational who presented between a history of newborn with congenital anomalies during the period 2002-2005, the Regional Hospital Dr. Ramón Carrillo de Santiago del Estero. We performed a descriptive, observational mode, retrospective and cross-sectional in a sample of 150 cases, obtained from a population of 285 newborns with birth defects. Data were collected from the Perinatal Clinical CLAP / WHO were used as statistical analysis, distribution of absolute and relative frequency tables and graphs with SPSS, version 11.5. The results identified a "repeated maternal profile" and were distributed most frequently observed malformations at birth according to the analyzed variables that emerged from the theoretical framework in question. In conclusion, I remain determined the need to continue studies of this disease and implement where possible, proper surveillance to enable early detection of those with an adequate quality of care for pregnant women and childbirth, to provide relevant and appropriate genetic counseling for this vulnerable group of our population.
