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Originally believed to be an omen for early widowhood, widow's peak, a V-shaped descending extension of the anterior hairline at the center of the forehead is now known to be a morphogenetic trait. Although in the majority of cases, widow's peak is a normal variant, its presence has also been associated with several genetic syndromes.
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Viudez , Femenino , Frente , HumanosRESUMEN
This study aims to address the role of focal adhesion proteins α- and ß-parvin in human colorectal carcinoma (CRC). Expression of α- and ß-parvin was examined by immunohistochemistry and real-time RT-PCR in a series of human CRC. Parvins were overexpressed in CRC and their expression correlated significantly with tumor invasion, lymph node metastasis, and disease stage. A significant positive correlation of parvins protein expression with overexpression of integrin-linked kinase, p-AKT, and nuclear ß-catenin, as well as with downregulation of E-cadherin was also observed. In conclusion, overexpression of α- and ß-parvin seems to be implicated in human colorectal cancer progression.
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Actinina/metabolismo , Neoplasias Colorrectales/patología , Proteínas de Microfilamentos/metabolismo , Actinina/genética , Adulto , Anciano , Anciano de 80 o más Años , Cadherinas/metabolismo , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Metástasis Linfática/genética , Masculino , Proteínas de Microfilamentos/genética , Persona de Mediana Edad , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Valores de Referencia , Adulto Joven , beta Catenina/metabolismoRESUMEN
INTRODUCTION: Data on nutrient and diet quality outcomes when additional beans are consumed as part of the typical American dietary pattern are scarce. The purpose of this study was to assess the effect of increased bean consumption, in the typical American dietary pattern, on the intake of shortfall nutrients and overall diet quality. METHODS: Using data from the US National Health and Nutrition Examination Survey, 2001-2018, the current analyses modeled the addition of one and two servings of canned and dried beans in all adults (N = 44,574; ≥19 y), younger adults (N = 23,554; 19-50 y) and older adults (N = 21,020; ≥51 y). The beans considered were kidney beans, black beans, chickpeas, and pinto beans. RESULTS: The modeling of beans to the typical American dietary pattern resulted in significant increases in the intake of several shortfall nutrients, including dietary fiber, potassium, magnesium, iron, folate, and choline (p's < 0.0001). Modeling 1 and 2 servings of beans daily to the US typical dietary pattern significantly increased overall diet quality in all adult age groups considered. Total diet quality, as measured by Healthy Eating Index-2015 scores, was 15-16 % greater with an additional serving of beans and 19-20 % higher with 2 servings of beans relative to the US typical dietary pattern (p values<0.0001). CONCLUSIONS: Dietary patterns that are rich in beans are associated with significantly higher diet quality scores and greater intake of shortfall nutrients, including nutrients of public health concern. Dietary guidance should consider the health benefits associated with the promotion of increased consumption of canned and dry beans in dietary patterns as benefits seen in younger adults continue to older adulthood.
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Dieta , Fabaceae , Encuestas Nutricionales , Humanos , Adulto , Persona de Mediana Edad , Dieta/estadística & datos numéricos , Adulto Joven , Estados Unidos , Femenino , Masculino , Anciano , Nutrientes , Fibras de la Dieta/administración & dosificación , Patrones DietéticosRESUMEN
Substantial evidence highlights divergences in immune responses between men and women. Women are more susceptible to autoimmunity, whereas men suffer from the more severe presentation of autoimmune disorders. The molecular mechanism of this sexual dimorphism remains elusive. Herein, we conducted a comprehensive analysis of sex differences in whole-blood gene expression focusing on alternative splicing (AS) events in systemic lupus erythematosus (SLE), which is a prototype sex-biased disease. This study included 79 SLE patients with active disease and 58 matched healthy controls who underwent whole-blood RNA sequencing. Sex differences in splicing events were widespread, existent in both SLE and a healthy state. However, we observed distinct gene sets and molecular pathways targeted by sex-dependent AS in SLE patients as compared to healthy subjects, as well as a notable sex dissimilarity in intron retention events. Sexually differential spliced genes specific to SLE patients were enriched for dynamic cellular processes including chromatin remodeling, stress and inflammatory responses. Remarkably, the extent of sexual differences in AS in the SLE patients and healthy individuals exceeded those in gene expression. Overall, this study reveals an unprecedent variation in sex-dependent splicing events in SLE and the healthy state, with potential implications for understanding the molecular basis of sexual dimorphism in autoimmunity.
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Empalme Alternativo , Lupus Eritematoso Sistémico , Humanos , Masculino , Femenino , Empalme Alternativo/genética , Autoinmunidad/genéticaRESUMEN
Early during preimplantation development and in heterogeneous mouse embryonic stem cells (mESC) culture, pluripotent cells are specified towards either the primed epiblast or the primitive endoderm (PE) lineage. Canonical Wnt signaling is crucial for safeguarding naive pluripotency and embryo implantation, yet the role and relevance of canonical Wnt inhibition during early mammalian development remains unknown. Here, we demonstrate that transcriptional repression exerted by Wnt/TCF7L1 promotes PE differentiation of mESCs and in preimplantation inner cell mass. Time-series RNA sequencing and promoter occupancy data reveal that TCF7L1 binds and represses genes encoding essential naive pluripotency factors and indispensable regulators of the formative pluripotency program, including Otx2 and Lef1. Consequently, TCF7L1 promotes pluripotency exit and suppresses epiblast lineage formation, thereby driving cells into PE specification. Conversely, TCF7L1 is required for PE specification as deletion of Tcf7l1 abrogates PE differentiation without restraining epiblast priming. Taken together, our study underscores the importance of transcriptional Wnt inhibition in regulating lineage specification in ESCs and preimplantation embryo development as well as identifies TCF7L1 as key regulator of this process.
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Conducción de Automóvil , Endodermo , Proteína 1 Similar al Factor de Transcripción 7 , Animales , Femenino , Ratones , Embarazo , Blastocisto , Diferenciación Celular , Estratos GerminativosRESUMEN
Bob Marley was a Jamaican singer, songwriter, and musician, considered one of the pioneers of reggae. In July 1977, he was diagnosed with acral lentiginous melanoma on his right great toe, which presented as a pigmented subungual lesion. Marley was advised to have his digit amputated, but he refused and opted for less invasive solutions. Unfortunately, he died at the age of 36 of metastatic disease in May 1981 after a 4-year battle with the disease. Marley has served as the posthumous poster child for skin cancer in people with skin of color for decades and has raised public awareness of this rare form of malignant melanoma.
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Melanoma , Neoplasias Cutáneas , Masculino , Niño , Humanos , Melanoma/diagnóstico , Neoplasias Cutáneas/diagnóstico , Piel/patología , Melanoma Cutáneo MalignoRESUMEN
A remarkable, yet poorly explained feature of Systemic Lupus Erythematosus (SLE) is the propensity to flare following a preceding period of disease inactivity. The clinical burden of lupus flares is substantial since they often tend to involve multiple or major organs, and carry a near two-fold increased risk for accrual of irreversible organ damage. The cellular and molecular mechanisms underlying the progression of SLE from inactive to active state remain ill-defined. Application of novel sequencing technologies together with cellular immunology assays, have illustrated the important role of multiple types of both innate and adaptive cells and associated pathways. We have previously described significant differences in the blood transcriptome of SLE patients at active versus inactive disease, and we have also defined genome regions (domains) with co-ordinated expression of genes implicated in the disease. In the present study, we aim to decipher the cellular and molecular basis of SLE exacerbations by utilising novel single-cell sequencing approaches, which allow us to characterise the transcriptional and epigenetic landscapes of thousands of cells in the peripheral blood of patients. The significance of the study lies in the detailed characterisation of the molecular and regulatory program of immune cell subpopulations that underlie progression from inactive to active SLE. Accordingly, our results may be exploited to identify biomarkers for disease monitoring and novel therapeutic targets.
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The TA-isoform of the p63 transcription factor (TAp63) has been reported to contribute to clinical aggressiveness in chronic lymphocytic leukemia (CLL) in a hitherto elusive way. Here, we sought to further understand and define the role of TAp63 in the pathophysiology of CLL. First, we found that elevated TAp63 expression levels are linked with adverse clinical outcomes, including disease relapse and shorter time-to-first treatment and overall survival. Next, prompted by the fact that TAp63 participates in an NF-κB/TAp63/BCL2 antiapoptotic axis in activated mature, normal B cells, we explored molecular links between TAp63 and BCL2 also in CLL. We documented a strong correlation at both the protein and the messenger RNA (mRNA) levels, alluding to the potential prosurvival role of TAp63. This claim was supported by inducible downregulation of TAp63 expression in the MEC1 CLL cell line using clustered regularly interspaced short palindromic repeats (CRISPR) system, which resulted in downregulation of BCL2 expression. Next, using chromatin immunoprecipitation (ChIP) sequencing, we examined whether BCL2 might constitute a transcriptional target of TAp63 and identified a significant binding profile of TAp63 in the BCL2 gene locus, across a genomic region previously characterized as a super enhancer in CLL. Moreover, we identified high-confidence TAp63 binding regions in genes mainly implicated in immune response and DNA-damage procedures. Finally, we found that upregulated TAp63 expression levels render CLL cells less responsive to apoptosis induction with the BCL2 inhibitor venetoclax. On these grounds, TAp63 appears to act as a positive modulator of BCL2, hence contributing to the antiapoptotic phenotype that underlies clinical aggressiveness and treatment resistance in CLL.
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Leucemia Linfocítica Crónica de Células B , Apoptosis/genética , Regulación de la Expresión Génica , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Factores de Transcripción , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Prostate cancer, the second most common malignancy in men, is characterized by high heterogeneity that poses several therapeutic challenges. Epithelial-mesenchymal transition (EMT) is a dynamic, reversible cellular process which is essential in normal embryonic morphogenesis and wound healing. However, the cellular changes that are induced by EMT suggest that it may also play a central role in tumor progression, invasion, metastasis, and resistance to current therapeutic options. These changes include enhanced motility and loss of cell-cell adhesion that form a more aggressive cellular phenotype. Moreover, the reverse process (MET) is a necessary element of the metastatic tumor process. It is highly probable that this cell plasticity reflects a hybrid state between epithelial and mesenchymal status. In this review, we describe the underlying key mechanisms of the EMT-induced phenotype modulation that contribute to prostate tumor aggressiveness and cancer therapy resistance, in an effort to provide a framework of this complex cellular process.
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In addition to increasing the complexity of the transcriptional output, alternative RNA splicing can lead to the reduction of mRNA translation or the production of non-functional or malfunctional proteins, thus representing a vital component of the gene regulation process. Herein, we set out to detect and characterize alternative splicing events that occur in whole-blood samples of patients with Systemic Lupus Erythematosus (SLE) as compared to healthy counterparts. Through the implementation of a computational pipeline on published RNA-sequencing data, we identified extensive changes in the transcription dynamics affecting a large number of genes. We found a predominance of intron retention events, with the majority introducing premature stop codons, suggestive of gene repression, in both inactive and active SLE patient samples. Alternative splicing affected a distinct set of genes from the ones detected as differentially expressed in the same comparisons, while alternatively spliced genes tended to reside in genome areas associated with increased gene co-expression. Functional analysis of genes affected by alternative splicing pointed towards particular functions related to metabolism and histone acetylation as of potential interest. Together, our findings underline the importance of incorporating alternative splicing analyses in the context of molecular characterization of complex diseases such as SLE.
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Empalme Alternativo/genética , Genoma Humano/genética , Lupus Eritematoso Sistémico/genética , Transcripción Genética/genética , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/genética , Humanos , Intrones/genética , Lupus Eritematoso Sistémico/patología , Masculino , RNA-SeqRESUMEN
AIMS: Epithelial-mesenchymal transition (EMT) has been known to play a significant role in tumour progression. Integrin-linked kinase (ILK) has been recently added to the growing list of EMT regulators that control some aspect of carcinogenesis. The aim was to study ILK expression and its relevance to EMT markers in human basal cell carcinoma (BCC). METHODS AND RESULTS: Paraffin-embedded tissue sections from 100 human BCC cases were processed by immunohistochemistry for the expression of ILK, E-cadherin, Snail, beta-catenin and alpha-smooth muscle actin (alpha-SMA). ILK overexpression was observed in 100% of cases and strongly correlated with tumour invasion and infiltrative BCC. Loss of membranous E-cadherin was found in 71% of cases while nuclear immunoreactivity for E-cadherin was also observed in 90% of the tumours. Snail, nuclear beta-catenin and alpha-SMA expression was detected in 100%, 99% and 97% of tumours, respectively. Aberrant expression of E-cadherin, nuclear beta-catenin and alpha-SMA correlated with BCC tumour invasion. Interestingly, there was a significant correlation between ILK expression and all the EMT markers examined. CONCLUSIONS: ILK overexpression in BCC is implicated in tumour progression probably through the induction of an EMT-related molecular profile. Nuclear localization of E-cadherin in BCC is also associated with aggressive tumour features.
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Carcinoma Basocelular/patología , Células Epiteliales/metabolismo , Células Madre Mesenquimatosas/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Neoplasias Cutáneas/patología , Biomarcadores de Tumor/metabolismo , Cadherinas/metabolismo , Carcinoma Basocelular/enzimología , Carcinoma Basocelular/metabolismo , Células Epiteliales/citología , Humanos , Inmunohistoquímica , Células Madre Mesenquimatosas/citología , Invasividad Neoplásica , Neoplasias Cutáneas/enzimología , Neoplasias Cutáneas/metabolismo , Factores de Transcripción de la Familia Snail , Factores de Transcripción/metabolismo , beta Catenina/metabolismoRESUMEN
STUDY DESIGN: The immunohistochemical profile of nuclear factor-κ B (NF-κB)/p50, NF-κB/p65, matrix metalloproteinase (MMP)-9, MMP-2, and urokinase-type plasminogen activator (u-PA) proteins was examined in spinal cord tissues coming from rabbits, which underwent chronic cervical spinal cord compression. OBJECTIVE: To study the potential role of NF-κB and extracellular matrix proteins under the chronic mechanical compression of the cervical spinal cord. SUMMARY OF BACKGROUND DATA: Cervical spondylotic myelopathy (CSM) is the most common cause of spinal cord dysfunction among adults older than 55 years. Neuronal loss, myelin destruction, axonal degeneration, and glial scar formation are the principal neuropathological features of CSM. However, the biologic pathways that lead to these features remain unclear. METHODS: In this study, we used a new animal experimental model of CSM developed in our laboratory. Briefly, after posterior cervical laminectomy, gradual and progressive compression (during 20 weeks) was achieved by introducing a piece of aromatic polyether (0.07 mm thick) under the C6 lamina in 15 New Zealand rabbits. In control animals (n = 15), the aromatic polyether was implanted and then removed after 60 seconds (sham operation). The immunoreactivity of p50 and p65 subunits of NF-kB, as well as that of MMP-2, MMP-9, and u-PA, was evaluated in paraffin-embedded spinal cord sections coming from both groups. The evaluation was performed using immunohistochemistry technique and the results were analyzed using SPSS for Windows, release 12.0 (SPSS Inc., Chicago, IL). RESULTS: Increased immunoreactivity of both NF-κB subunits, p50 and p65, as well as MMP-2, MMP-9, and u-PA was demonstrated in animals with CSM in comparison with controls. Statistical analysis of the results revealed strong positive correlation between NF-κB subunits immunoreactivity and that of MMP-9, MMP-2, and u-PA. CONCLUSION: There is a strong correlation between the immunoexpression of NF-κB/p50, NF-κB/p65, MMP-2, MMP-9, u-PA, and CSM.