HuR (ELAVL1) Stabilizes SOX9 mRNA and Promotes Migration and Invasion in Breast Cancer Cells.

RNA-binding proteins play diverse roles in cancer, influencing various facets of the disease, including proliferation, apoptosis, angiogenesis, senescence, invasion, epithelial-mesenchymal transition (EMT), and metastasis. HuR, a known RBP, is recognized for stabilizing mRNAs containing AU-rich elements (AREs), although its complete repertoire of mRNA targets remains undefined. Through a bioinformatics analysis of the gene expression profile of the Hs578T basal-like triple-negative breast cancer cell line with silenced HuR, we have identified SOX9 as a potential HuR-regulated target. SOX9 is a transcription factor involved in promoting EMT, metastasis, survival, and the maintenance of cancer stem cells (CSCs) in triple-negative breast cancer. Ribonucleoprotein immunoprecipitation assays confirm a direct interaction between HuR and SOX9 mRNA. The half-life of SOX9 mRNA and the levels of SOX9 protein decreased in cells lacking HuR. Cells silenced for HuR exhibit reduced migration and invasion compared to control cells, a phenotype similar to that described for SOX9-silenced cells.

New Functions of Intracellular LOXL2: Modulation of RNA-Binding Proteins.

Lysyl oxidase-like 2 (LOXL2) was initially described as an extracellular enzyme involved in extracellular matrix remodeling. Nevertheless, numerous recent reports have implicated intracellular LOXL2 in a wide variety of processes that impact on gene transcription, development, differentiation, proliferation, migration, cell adhesion, and angiogenesis, suggesting multiple different functions for this protein. In addition, increasing knowledge about LOXL2 points to a role in several types of human cancer. Moreover, LOXL2 is able to induce the epithelial-to-mesenchymal transition (EMT) process-the first step in the metastatic cascade. To uncover the underlying mechanisms of the great variety of functions of intracellular LOXL2, we carried out an analysis of LOXL2's nuclear interactome. This study reveals the interaction of LOXL2 with numerous RNA-binding proteins (RBPs) involved in several aspects of RNA metabolism. Gene expression profile analysis of cells silenced for LOXL2, combined with in silico identification of RBPs' targets, points to six RBPs as candidates to be substrates of LOXL2's action, and that deserve a more mechanistic analysis in the future. The results presented here allow us to hypothesize novel LOXL2 functions that might help to comprehend its multifaceted role in the tumorigenic process.

Telomerase RNA plays a major role in the completion of the life cycle in Ustilago maydis and shares conserved domains with other Ustilaginales.

The RNA subunit of telomerase is an essential component whose primary sequence and length are poorly conserved among eukaryotic organisms. The phytopathogen Ustilago maydis is a dimorphic fungus of the order Ustilaginales. We analyzed several species of Ustilaginales to computationally identify the TElomere RNA (TER) gene ter1. To confirm the identity of the TER gene, we disrupted the gene and characterized telomerase-negative mutants. Similar to catalytic TERT mutants, ter1Δ mutants exhibit phenotypes of growth delay, telomere shortening and low replicative potential. ter1-disrupted mutants were unable to infect maize seedlings in heterozygous crosses and showed defects such as cell cycle arrest and segregation failure. We concluded that ter1, which encodes the TER subunit of the telomerase of U. maydis, have similar and perhaps more extensive functions than trt1.

Strength, Elastic Properties and Fiber-Matrix Interaction Mechanism in Geopolymer Composites.

The current geopolymers have limited mechanical strength against the effect of tension, which makes them susceptible to brittle failure. However, owing to their potential as a sustainable construction material, there is growing interest in improving the poor mechanical properties of geopolymers. This study experimentally investigated crucial properties of polypropylene-fiber-reinforced fly ash-based geopolymer composites. The effects of polypropylene fibers (PPF) addition (0.5%, 1.0% and 1.5% by volume) on the mechanical properties of the geopolymer composites were investigated with respect to compressive and flexural strength, deformation behavior of Young's and shear moduli, and resilience capacity. In addition, scanning electron microscopy was performed to establish the morphology of the geopolymeric matrix and the fiber-matrix interfacial interaction. The addition of PPF significantly increased the flexural strength: compared with the control, at 7 days it was 27% greater for the 0.5% PPF composite and 65% greater for the 1.0% PPF composite. By 14 days it was 31% and 61% greater, respectively. By contrast, the 1.5% PPF composite had lower strength parameters compared with the control because the fiber dispersion increased the porosity. Similar trends were seen for resilience. The SEM observations showed the dispersion of the fibers and helped elucidate the fiber-matrix interaction mechanism.

FOXE1 regulates migration and invasion in thyroid cancer cells and targets ZEB1.

FOXE1 is a thyroid-specific transcription factor essential for thyroid gland development and maintenance of the differentiated state. Interestingly, a strong association has been recently described between FOXE1 expression and susceptibility to thyroid cancer, but little is known about the mechanisms underlying FOXE1-induced thyroid tumorigenesis. Here, we used a panel of human thyroid cancer-derived cell lines covering the spectrum of thyroid cancer phenotypes to examine FOXE1 expression and to test for correlations between FOXE1 expression, the allele frequency of two SNPs and a length polymorphism in or near the FOXE1 locus associated with cancer susceptibility, and the migration ability of thyroid cancer cell lines. Results showed that FOXE1 expression correlated with differentiation status according to histological sub-type, but not with SNP genotype or cell migration ability. However, loss-and-gain-of-function experiments revealed that FOXE1 modulates cell migration, suggesting a role in epithelial-to-mesenchymal transition (EMT). Our previous genome-wide expression analysis identified Zeb1, a major EMT inducer, as a putative Foxe1 target gene. Indeed, gene silencing of FOXE1 decreased ZEB1 expression, whereas its overexpression increased ZEB1 transcriptional activity. FOXE1 was found to directly interact with the ZEB1 promoter. Lastly, ZEB1 silencing decreased the ability of thyroid tumoral cells to migrate and invade, pointing to its importance in thyroid tumor mestastases. In conclusion, we have identified ZEB1 as a bona fide target of FOXE1 in thyroid cancer cells, which provides new insights into the role of FOXE1 in regulating cell migration and invasion in thyroid cancer.

Impaired Gene Expression Due to Iodine Excess in the Development and Differentiation of Endoderm and Thyroid Is Associated with Epigenetic Changes.

Background: Thyroid hormone (TH) synthesis is essential for the control of development, growth, and metabolism in vertebrates and depends on a sufficient dietary iodine intake. Importantly, both iodine deficiency and iodine excess (IE) impair TH synthesis, causing serious health problems especially during fetal/neonatal development. While it is known that IE disrupts thyroid function by inhibiting thyroid gene expression, its effects on thyroid development are less clear. Accordingly, this study sought to investigate the effects of IE during the embryonic development/differentiation of endoderm and the thyroid gland. Methods: We used the murine embryonic stem (ES) cell model of in vitro directed differentiation to assess the impact of IE on the generation of endoderm and thyroid cells. Additionally, we subjected endoderm and thyroid explants obtained during early gestation to IE and evaluated gene and protein expression of endodermal markers in both models. Results: ES cells were successfully differentiated into endoderm cells and, subsequently, into thyrocytes expressing the specific thyroid markers Tshr, Slc5a5, Tpo, and Tg. IE exposure decreased the messenger RNA (mRNA) levels of the main endoderm markers Afp, Crcx4, Foxa1, Foxa2, and Sox17 in both ES cell-derived endoderm cells and embryonic explants. Interestingly, IE also decreased the expression of the main thyroid markers in ES cell-derived thyrocytes and thyroid explants. Finally, we demonstrate that DNA methyltransferase expression was increased by exposure to IE, and this was accompanied by hypermethylation and hypoacetylation of histone H3, pointing to an association between the gene repression triggered by IE and the observed epigenetic changes. Conclusions: These data establish that IE treatment is deleterious for embryonic endoderm and thyroid gene expression.

First report of a KELnull phenotype in Peru and a lesson of invisible genetic disparity.

Blood banks in developing countries have limited capability to typify common blood groups creating disparities in the access to blood units for patients with rare blood genotypes. We report the case of a Peruvian woman with metastatic breast cancer with KELnull phenotype (K0), a rare blood group characterized by the lack of expression of all Kell antigens on the red blood cells (RBCs). The molecular studies identified that the patient's RBCs were homozygous for the nonsense c.1546C > T mutation predicted to encode p.Arg516Ter (KEL*02 N.17 allele), which confirmed the K0 phenotype. We conducted a local and international search of compatible blood units. Finally, the Japanese Red Cross donated the blood units for the patient. We present here the first report for a K0 phenotype in Peru and the challenging genetic disparities that many patients have to face to access to blood units in our country.

Ameloblastoma uniquístico plexiforme: a propósito de un caso / Plexiform unicystic ameloblastoma: a propos of a case

El ameloblastoma es un tumor odontogénico benigno de origen epitelialcon estroma fi broso maduro sin ectomesénquima odontogénico, decomportamiento localmente agresivo e infi ltrante con alta capacidad de recidiva. Representa entre 11 y 13 por ciento de los tumores odontogénicosmandibulares y 1 por ciento de los tumores y quistes maxilomandibulares. El tratamiento debe orientarse de acuerdo con el potencial del tumor,las características del crecimiento según su variable clínica y el tipo histológico. Debe ser un tratamiento que asegure un mejor pronóstico para el paciente

The ameloblastoma is a benign odontogenic tumor of epithelial origin with mature fi brous stroma, without odontogenic ectomesenchyme. It exhibits locally aggressive and invasive behavior, with a high level of recurrence. Ameloblastomata account for between 11 and 13% of mandibular odontogenic tumors, and 1% of maxillo-mandibular tumors and cysts. Treatment should be guided by the potential of the tumor and its growth characteristics based on the clinical variable and histological type, the preferred treatment being that which ensures the best prognosis for the patient.

Identification of proteins associated with amyloidosis by polarity index method.

There is a natural protein form, insoluble and resistant to proteolysis, adopted by many proteins independently of their amino acid sequences via specific misfolding-aggregation process. This dynamic process occurs in parallel with or as an alternative to physiologic folding, generating toxic protein aggregates that are deposited and accumulated in various organs and tissues. These proteinaceous deposits typically represent bundles of ß-sheet-enriched fibrillar species known as the amyloid fibrils that are responsible for serious pathological conditions, including but not limited to neurodegenerative diseases, grouped under the term amyloidoses. The proteins that might adopt this fibrillar conformation are some globular proteins and natively unfolded (or intrinsically disordered) proteins. Our work shows that intrinsically disordered and intrinsically ordered proteins can be reliably identified, discriminated, and differentiated by analyzing their polarity profiles generated using a computational tool known as the polarity index method (Polanco & Samaniego, 2009; Polanco et al., 2012; 2013; 2013a; 2014; 2014a; 2014b; 2014c; 2014d). We also show that proteins expressed in neurons can be differentiated from proteins in these two groups based on their polarity profiles, and also that this computational tool can be used to identify proteins associated with amyloidoses. The efficiency of the proposed method is high (i.e. 70%) as evidenced by the analysis of peptides and proteins in the APD2 database (2012), AVPpred database (2013), and CPPsite database (2013), the set of selective antibacterial peptides from del Rio et al. (2001), the sets of natively unfolded and natively folded proteins from Oldfield et al. (2005), the set of human revised proteins expressed in neurons, and non-human revised proteins expressed in neurons, from the Uniprot database (2014), and also the set of amyloidogenic proteins from the AmyPDB database (2014).

Evidencia científica de la relación entre acoso laboral y depresión / Evidence based relationship between mobbing and depression

Introducción: El Acoso laboral es una epidemia silenciosa que no solamente afecta a la motivación y a la productividad de los trabajadores, sino que también, afecta negativamente a su víctimas en aspectos psicosociales siendo la depresión una de sus consecuencias. Objetivos: El objetivo es identificar la evidencia científica conocida sobre la relación existente entre el acoso laboral y la depresión. Metodología: Se formularon una serie de ecuaciones de búsqueda con los términos: Mobbing, Depression, Workplace Bullying, Harassment, Depresión y Acoso Laboral, que se aplicaron a diferentes bases de datos bibliográficas (IBECS, LILACS, The Cochrane Library Plus, Scielo, WHOLIS, OSH Update), que permitió la identificación de 36 referencias de las cuales 8 cumplieron los criterios de inclusión. En función de los objetivos planteados se extrajo la información respectiva después de su revisión a texto completo. Resultados: La prevalencia de acoso laboral fluctuó entre un 11,9% y un 81% según los países en los que se realizó el estudio. Ser mujer, tener estudios universitarios y la antigüedad o experiencia en el puesto de trabajo son factores que determinaron una mayor vulnerabilidad para sufrir acoso. El perfil del acosador es: ser de sexo masculino y, generalmente, de categoría superior a la víctima; siendo el abuso verbal, el hostigamiento y el aumento de la carga laboral las estrategias de acoso más utilizadas. En todos los estudios se encontró una relación positiva entre el acoso y la depresión. Conclusiones: La revisión realizada, no permite demostrar una relación de causalidad entre el acoso y depresión. La reproducibilidad en los resultados de los estudios evidencian la existencia de una asociación entre acoso y depresión, siendo necesario el promover estudios de diseño longitudinal que puedan demostrar, o no, una asociación causal (AU)

Introduction: Workplace bullying is a silent epidemic that affects motivation and productivity of workers, but there are also consequences in psychosocial level being depression one of its. Objectives: The objective is to identify the scientific evidence on the relationship between bullying and depression. Methods: We formulated a set of equations search using the terms: Mobbing, Depression, Workplace Bullying, Harassment, Workplace Bullying Depression, which were applied to different bibliographic databases (IBECS, LILACS, The Cochrane Library Plus, SciELO, WHOLIS , OSH Update), which allowed the identification of 36 references of which 8 met the inclusion criteria. In relation with each objectives the information was extracted after full-text review. Results: The prevalence of bullying ranged between 11.9% and 81% depending on the country in which the study was conducted. Female, having a college education and seniority or experience in the job are factors that determined an increased vulnerability to harassment. The profile of the harasser is: male, and generally superior to the victim, verbal abuse, harassment and increased workload are the bullying strategies most used. All studies evidence a positive relationship between bullying and depression. Conclusions: The review, does not establish a causal relationship between bullying and depression. The reproducibility of the results of the studies show the existence of an association between bullying and depression, being necessary to promote longitudinal studies that could show, or not, a causal association (AU)

Expression of hypothalamic regulatory peptides in thyroid C cells of different mammals.

Besides intervening in calcium homeostasis by means of calcitonin, C cells are also implicated in the synthesis of an increasing number of regulatory peptides that could exert a paracrine regulation on the neighbouring follicular cells. Among the latest peptides reported in C cells, there are several characteristic hypothalamic peptides, such as TRH, CART, and ghrelin, which are mainly involved in the regulation of the metabolism at hypothalamic-pituitary-thyroid axis. The main aim of the present work has been to study the synthesis of the referred hypothalamic peptides by normal and neoplastic C cells of different mammals as well as in C-cell lines of both rat (CA-77, 6-23) and human (TT) origins in order to elucidate whether this is a fact in this kind of vertebrates. With that objective, we have applied the immunoperoxidase technique to analyze the presence of TRH, CART, ghrelin, and somatostatin in thyroid tissues of different species, and immunofluorescence to study those same peptides in C-cell cultures. Furthermore, we have investigated their expression at mRNA level by RT-PCR analysis. Our results demonstrate immunocolocalization of CART, ghrelin, somatostatin and TRH with calcitonin in normal C cells of different mammals, as well as in rat and human neoplastic C cells. We also confirm the expression of those peptides in rat and human C-cell lines by RT-PCR. Consequently, we can conclude that the synthesis of those peptides by C cells is a general event characteristic of the thyroid gland in mammals.

Melatonin-synthesizing enzymes and melatonin receptor in rat thyroid cells.

Melatonin is an indoleamine with a wide spectrum of biological activities other than transmitting photoperiod information, including antioxidant, oncostatic, anti-aging and immunomodulatory properties. Although melatonin is synthesized mainly in the pineal gland, other tissues have the same capacity. In the present study, we examined whether two key enzymes in melatonin biosynthesis, arylalkylamine Nacetyltransferase (AANAT) and hydroxyindole-O-methyltransferase (HIOMT) and its receptor MT1 are expressed in the two endocrine thyroid cells of the rat, follicular cells and C cells. Reverse transcriptase polymerase chain reaction analyses demonstrated that both AANAT and HIOMT mRNAs are expressed in the rat thyroid C-cells, and MT1 expression has been detected in C cells and follicular cells. Immunofluorescence revealed that AANAT protein is localized in C-cell cytoplasm, and MT1 protein in both cell populations. These findings demonstrate that the rat thyroid expresses AANAT, HIOMT, and its receptor MT1, showing that C cells are the main melatonin-synthesizing sites in the thyroid. This local C-cell-secreted melatonin may protect follicular cells from the oxidative stress inherent to the thyroid gland, and could also have paracrine and autocrine functions.

Cutting edge: IL-21 derived from human follicular helper T cells acts as a survival factor for secondary lymphoid organ, but not for bone marrow, plasma cells.

IL-21 induces the differentiation of activated B lymphocytes into plasma cells (PC), but its direct effect on PC remains uncertain. This study analyzes the role of IL-21 on human in vivo-generated PC. IL-21R was clearly expressed on PC from the human tonsil, the lymph node, and the spleen (secondary lymphoid organs [SLO]) but barely on terminally mature bone marrow PC. IL-21 enhanced Ig secretion by isolated SLO PC but not bone marrow PC. Tonsillar T follicular helper (Tfh) lymphocytes are known to secrete IL-21. Purified Tfh cells induced a marked increase of Ig production by tonsillar PC, and this effect was impaired when endogenous IL-21 production was blocked. IL-21 provoked a rapid and transient phosphorylation of STAT3 in tonsillar PC. Tfh cells or exogenous IL-21 reduce tonsillar PC apoptosis and increases PC recovery but does not modify their nonproliferating status. These results suggest that IL-21 derived from Tfh cells acts as a survival factor for SLO PC in vivo.

Functional expression of the thyrotropin receptor in C cells: new insights into their involvement in the hypothalamic-pituitary-thyroid axis.

Thyroid C cells, or parafollicular cells, are mainly known for producing calcitonin, a hormone involved in calcium homeostasis with hypocalcemic and hypophosphatemic effects. Classically, the main endocrine activity of this cell population has been believed to be restricted to its roles in serum calcium and bone metabolism. Nonetheless, in the last few years evidence has been accumulating in the literature with regard to local regulatory peptides secreted by C cells, such as somatostatin, ghrelin, thyrotropin releasing hormone or the recently described cocaine- and amphetamine-related transcript, which could modify thyroid function. As thyrotropin is the main hormone controlling the hypothalamic-pituitary-thyroid axis and, accordingly, thyroid function, we have examined the functional expression of the thyrotropin receptor in C-cell lines and in thyroid tissues. We have found that rat and human C-cell lines express the thyrotropin receptor at both mRNA and protein levels. Furthermore, incubation of C cells with thyrotropin resulted in a 10-fold inhibition of thyrotropin-receptor expression, and a concomitant decrease of the steady-state mRNA levels for calcitonin and calcitonin gene-related peptide determined by quantitative real-time PCR was found. Finally, thyrotropin receptor expression by C cells was confirmed at protein level in both normal and pathological thyroid tissues by immunohistochemistry and immunofluorescence. These results confirm that C cells, under regulation by thyrotropin, are involved in the hypothalamic-pituitary-thyroid axis and suggest a putative role in local fine-tuning of follicular cell activity.