Bladder cancer is lethal in its advanced, muscle-invasive phase with very limited therapeutic advances
. Recent molecular characterization has defined new (epi)genetic drivers and potential targets ...for bladder cancer
. The immune checkpoint inhibitors have shown remarkable efficacy but only in a limited fraction of bladder cancer patients
. Here, we show that high G9a (EHMT2) expression is associated with poor clinical outcome in bladder cancer and that targeting G9a/DNMT methyltransferase activity with a novel inhibitor (CM-272) induces apoptosis and immunogenic cell death. Using an immunocompetent quadruple-knockout (Pten
; Trp53
; Rb1
; Rbl1
) transgenic mouse model of aggressive metastatic, muscle-invasive bladder cancer, we demonstrate that CM-272 + cisplatin treatment results in statistically significant regression of established tumors and metastases. The antitumor effect is significantly improved when CM-272 is combined with anti-programmed cell death ligand 1, even in the absence of cisplatin. These effects are associated with an endogenous antitumor immune response and immunogenic cell death with the conversion of a cold immune tumor into a hot tumor. Finally, increased G9a expression was associated with resistance to programmed cell death protein 1 inhibition in a cohort of patients with bladder cancer. In summary, these findings support new and promising opportunities for the treatment of bladder cancer using a combination of epigenetic inhibitors and immune checkpoint blockade.
Bladder cancer is a current clinical and social problem. At diagnosis, most patients present with nonmuscle-invasive tumors, characterized by a high recurrence rate, which could progress to ...muscle-invasive disease and metastasis. Bone morphogenetic protein (BMP)-dependent signaling arising from stromal bladder tissue mediates urothelial homeostasis by promoting urothelial cell differentiation. However, the possible role of BMP ligands in bladder cancer is still unclear.
Tumor and normal tissue from 68 patients with urothelial cancer were prospectively collected and analyzed for expression of BMP and macrophage markers. The mechanism of action was assessed
by experiments with bladder cancer cell lines and peripheral blood monocyte-derived macrophages.
We observed
expression is associated and favored type II macrophage differentiation.
experiments showed that both recombinant BMP4 and BMP4-containing conditioned media from bladder cancer cell lines favored monocyte/macrophage polarization toward M2 phenotype macrophages, as shown by the expression and secretion of IL10. Using a series of human bladder cancer patient samples, we also observed increased expression of
in advanced and undifferentiated tumors in close correlation with epithelial-mesenchymal transition (EMT). However, the p-Smad 1,5,8 staining in tumors showing EMT signs was reduced, due to the increased miR-21 expression leading to reduced
expression.
These findings suggest that BMP4 secretion by bladder cancer cells provides the M2 signal necessary for a protumoral immune environment. In addition, the repression of
by miR-21 makes the tumor cells refractory to the prodifferentiating actions mediated by BMP ligands, favoring tumor growth.
.
Los debates electorales han sido extensamente estudiados en los Estados Unidos. Sin embargo, no se conoce ningún estudio dedicado a analizar y evaluar la investigación sobre debates electorales en ...España. Por este motivo, el objetivo de este trabajo es conocer el estado actual de la investigación sobre este campo. Para ello, se utilizó el análisis bibliométrico de los artículos de revistas, los capítulos de libros, los libros, las actas de congresos y las tesis publicados en los últimos veinticinco años (1993-2018). Se consultaron cinco bases de datos: Dialnet, ISOC, Teseo, Scopus y Web of Science. El número de documentos fue de 107. Se analizaron la tipología documental, la autoría, la evolución temporal de las publicaciones y el idioma. En cuanto a los artículos, se estudió la distribución por revistas, los centros de adscripción, las principales líneas de investigación, el debate más investigado, las disciplinas, el tipo de investigación y la técnica más utilizada. Los resultados muestran, entre otras cuestiones, que la investigación se difunde principalmente a través de los artículos de revistas científicas; la colaboración entre autores es poco frecuente; la lengua más utilizada es el español, y la presencia en revistas con factor de impacto es muy baja.
Bladder Cancer (BC) represents a clinical and social challenge due to its high incidence and recurrence rates, as well as the limited advances in effective disease management. Currently, a ...combination of cytology and cystoscopy is the routinely used methodology for diagnosis, prognosis and disease surveillance. However, both the poor sensitivity of cytology tests as well as the high invasiveness and big variation in tumour stage and grade interpretation using cystoscopy, emphasizes the urgent need for improvements in BC clinical guidance. Liquid biopsy represents a new non-invasive approach that has been extensively studied over the last decade and holds great promise. Even though its clinical use is still compromised, multiple studies have recently focused on the potential application of biomarkers in liquid biopsies for BC, including circulating tumour cells and DNA, RNAs, proteins and peptides, metabolites and extracellular vesicles. In this review, we summarize the present knowledge on the different types of biomarkers, their potential use in liquid biopsy and clinical applications in BC.
Targeted therapies are the state of the art in oncology today, and every year new Tumor-associated antigens (TAAs) are developed for preclinical research and clinical trials, but few of them really ...change the therapeutic scenario. Difficulties, either to find antigens that are solely expressed in tumors or the generation of good binders to these antigens, represent a major bottleneck. Specialized cellular mechanisms, such as differential splicing and glycosylation processes, are a good source of neo-antigen expression. Changes in these processes generate surface proteins that, instead of showing decreased or increased antigen expression driven by enhanced mRNA processing, are aberrant in nature and therefore more specific targets to elicit a precise anti-tumor therapy. Here, we present promising TAAs demonstrated to be potential targets for cancer monitoring, targeted therapy and the generation of new immunotherapy tools, such as recombinant antibodies and chimeric antigen receptor (CAR) T cell (CAR-T) or Chimeric Antigen Receptor-Engineered Natural Killer (CAR-NK) for specific tumor killing, in a wide variety of tumor types. Specifically, this review is a detailed update on TAAs CD44v6, STn and O-GD2, describing their origin as well as their current and potential use as disease biomarker and therapeutic target in a diversity of tumor types.
Hamelia patens, is a plant traditionally used to treat a variety of conditions among the Huastec people of Mexico. The objective of this study is to characterize the phenolic content and critically ...examine the antimicrobial activity of leaf extracts H. patens, obtained by maceration, Soxhlet and percolation, using ethanol as 70% solvent. Phenolic compounds are characterized by liquid chromatography, coupled to a High Resolution Mass Spectrometry, and the antimicrobial activity was studied from the inhibitory effect of each extract for Escherichia coli, Staphylococcus aureus, Salmonella typhi and S. paratyphi, and by the Minimum Bactericidal Concentration, the percentage of activity and the Index of Bacterial Susceptibility of each extract. The phenolic compound identified in different concentrations in the three extracts was epicatechin. The extracts obtained by the three methods had antimicrobial activity, however, there was no significant difference (p<0.05) between the Minimum Bactericidal Concentration of the extracts obtained by maceration, percolation and Soxhlet. The results of this study contribute to the body of knowledge on the use of extracts in controlling microorganisms with natural antimicrobials.
Bladder cancer is a clinical and social problem due to its high incidence and recurrence rates. It frequently appears in elderly patients showing other medical comorbidities that hamper the use of ...standard chemotherapy. We evaluated the activity of CDK4/6 inhibitor as a new therapy for patients unfit for cisplatin (CDDP).
Bladder cancer cell lines were tested for
sensitivity to CDK4/6 inhibition. A novel metastatic bladder cancer mouse model was developed and used to test its
activity.
Cell lines tested were sensitive to CDK4/6 inhibition, independent on
gene status. Transcriptome analyses and knockdown experiments revealed a major role for FOXM1 in this response. CDK4/6 inhibition resulted in reduced FOXM1 phosphorylation
and
and showed synergy with CDDP, allowing a significant tumor regression. FOXM1 exerted important oncogenic roles in bladder cancer.
CDK4/6 inhibitors, alone or in combination, are a novel therapeutic strategy for patients with advanced bladder cancer previously classified as unfit for current treatment options.
EZH2 in Bladder Cancer, a Promising Therapeutic Target Martínez-Fernández, Mónica; Rubio, Carolina; Segovia, Cristina ...
International Journal of Molecular Sciences,
11/2015, Letnik:
16, Številka:
11
Journal Article, Book Review
Recenzirano
Odprti dostop
Bladder Cancer (BC) represents a current clinical and social challenge. The recent studies aimed to describe the genomic landscape of BC have underscored the relevance of epigenetic alterations in ...the pathogenesis of these tumors. Among the epigenetic alterations, histone modifications occupied a central role not only in cancer, but also in normal organism homeostasis and development. EZH2 (Enhancer of Zeste Homolog 2) belongs to the Polycomb repressive complex 2 as its catalytic subunit, which through the trimethylation of H3 (Histone 3) on K27 (Lysine 27), produces gene silencing. EZH2 is frequently overexpressed in multiple tumor types, including BC, and plays multiple roles besides the well-recognized histone mark generation. In this review, we summarize the present knowledge on the oncogenic roles of EZH2 and its potential use as a therapeutic target, with special emphasis on BC pathogenesis and management.
Bladder cancer (BC) is the most common neoplasia of the urothelial tract. Due to its high incidence, prevalence, recurrence and mortality, it remains an unsolved clinical and social problem. The ...treatment of BC is challenging and, although immunotherapies have revealed potential benefit in a percentage of patients, it remains mostly an incurable disease at its advanced state. Epigenetic alterations, including aberrant DNA methylation, altered chromatin remodeling and deregulated expression of non-coding RNAs are common events in BC and can be driver events in BC pathogenesis. Accordingly, these epigenetic alterations are now being used as potential biomarkers for these disorders and are being envisioned as potential therapeutic targets for the future management of BC. In this review, we summarize the recent findings in these emerging and exciting new aspects paving the way for future clinical treatment of this disease.
Resumen (analítico)Las paternidades en universitarios conllevan vulnerabilidades, cambios y dicotomías. Comprender los significados atribuidos a su paternidad implicó basarse en principios del ...interaccionismo simbólico a partir de la descripción de cotidianidad, relaciones y cambios en su proyecto de vida. La metodología se basó en el enfoque de teoría fundamentada. Se aplicaron entrevistas semiestructuradas a profundidad a ocho estudiantes de pregrado de una universidad pública enColombia. Ser joven, padre y estudiante implica asumir múltiples actividades que llevan a reducir la paternidad a una responsabilidad predominantemente económica. Generando tensiones en los jóvenes quienes se ven ante la necesidad de intensificar o incursionar en mercados laborales precarizados que afectan la salud mental y física; por ende, repercuten en el rendimiento académico y perpetúan los roles tradicionales atribuidos a los géneros.
Palabras clave: Padres, joven, estudiante, universidad.
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