Impact of HuR inhibition by the small molecule MS-444 on colorectal cancer cell tumorigenesis.

Colorectal cancer (CRC) is the third most common cancer and a leading cause of cancer-related mortality. Observed during CRC tumorigenesis is loss of post-transcriptional regulation of tumor-promoting genes such as COX-2, TNFα and VEGF. Overexpression of the RNA-binding protein HuR (ELAVL1) occurs during colon tumorigenesis and is abnormally present within the cytoplasm, where it post-transcriptionally regulates genes through its interaction with 3\u27UTR AU-rich elements (AREs). Here, we examine the therapeutic potential of targeting HuR using MS-444, a small molecule HuR inhibitor. Treatment of CRC cells with MS-444 resulted in growth inhibition and increased apoptotic gene expression, while similar treatment doses in non-transformed intestinal cells had no appreciable effects. Mechanistically, MS-444 disrupted HuR cytoplasmic trafficking and released ARE-mRNAs for localization to P-bodies, but did not affect total HuR expression levels. This resulted in MS-444-mediated inhibition of COX-2 and other ARE-mRNA expression levels. Importantly, MS-444 was well tolerated and inhibited xenograft CRC tumor growth through enhanced apoptosis and decreased angiogenesis upon intraperitoneal administration. In vivo treatment of MS-444 inhibited HuR cytoplasmic localization and decreased COX-2 expression in tumors. These findings provide evidence that therapeutic strategies to target HuR in CRC warrant further investigation in an effort to move this approach to the clinic

Actores Secundarios

info:eu-repo/semantics/publishedVersio

Actores Secundarios

info:eu-repo/semantics/publishedVersio

The genomic diversification of grapevine clones.

BACKGROUND:Vegetatively propagated clones accumulate somatic mutations. The purpose of this study was to better appreciate clone diversity and involved defining the nature of somatic mutations throughout the genome. Fifteen Zinfandel winegrape clone genomes were sequenced and compared to one another using a highly contiguous genome reference produced from one of the clones, Zinfandel 03. RESULTS:Though most heterozygous variants were shared, somatic mutations accumulated in individual and subsets of clones. Overall, heterozygous mutations were most frequent in intergenic space and more frequent in introns than exons. A significantly larger percentage of CpG, CHG, and CHH sites in repetitive intergenic space experienced transition mutations than in genic and non-repetitive intergenic spaces, likely because of higher levels of methylation in the region and because methylated cytosines often spontaneously deaminate. Of the minority of mutations that occurred in exons, larger proportions of these were putatively deleterious when they occurred in relatively few clones. CONCLUSIONS:These data support three major conclusions. First, repetitive intergenic space is a major driver of clone genome diversification. Second, clones accumulate putatively deleterious mutations. Third, the data suggest selection against deleterious variants in coding regions or some mechanism by which mutations are less frequent in coding than noncoding regions of the genome

Efficacy of capacitive resistive monopolar radiofrequency in the physiotherapeutic treatment of chronic pelvic pain syndrome : study protocol for a randomized controlled trial

Chronic pelvic pain syndrome (CPPS) is a multifactorial disorder that affects 5.7% to 26.6% of women and 2.2% to 9.7% of men, characterized by hypersensitivity of the central and peripheral nervous system affecting bladder and genital function. People with CPPS have much higher rates of psychological disorders (anxiety, depression, and catastrophizing) that increase the severity of chronic pain and worsen quality of life. Myofascial therapy, manual therapy, and treatment of trigger points are proven therapeutic options for this syndrome. This study aims to evaluate the efficacy of capacitive resistive monopolar radiofrequency (CRMRF) at 448kHz as an adjunct treatment to other physiotherapeutic techniques for reducing pain and improving the quality of life of patients with CPPS. This triple-blind (1:1) randomized controlled trial will include 80 women and men with CPPS. Participants will be randomized into a CRMRF activated group or a CRMRF deactivated group and receive physiotherapeutic techniques and pain education. The groups will undergo treatment for 10 consecutive weeks. At the beginning of the trial there will be an evaluation of pain intensity (using VAS), quality of life (using the SF-12), kinesiophobia (using the TSK-11), and catastrophism (using the PCS), as well as at the sixth and tenth sessions. The results of this study will show that CRMRF benefits the treatment of patients with CPPS, together with physiotherapeutic techniques and pain education. These results could offer an alternative conservative treatment option for these patients. ClinicalTrials.gov . Registered on 8 January 2019. The online version contains supplementary material available at 10.1186/s13063-021-05321-6

SCORE and REGICOR function charts underestimate the cardiovascular risk in Spanish patients with rheumatoid arthritis

Introduction: Our objective was to determine which one of the two function charts available in Spain to calculate cardiovascular (CV) risk, Systematic COronary Risk Evaluation (SCORE) or Framingham-REgistre GIroní del COR (REGICOR), should be used in patients with rheumatoid arthritis (RA). Methods: A series of RA patients seen over a one-year period without history of CV events were assessed. SCORE, REGICOR, modified (m)SCORE and mREGICOR according to the European League Against Rheumatism (EULAR) recommendations were applied. Carotid ultrasonography (US) was performed. Carotid intima-media thickness (cIMT) > 0.90 mm and/or carotid plaques were used as the gold standard test for severe subclinical atherosclerosis and high CV risk (US+). The area under the receiver operating curves (AUC) for the predicted risk for mSCORE and mREGICOR were calculated according to the presence of severe carotid US findings (US+). Results: We included 370 patients (80% women; mean age 58.9 ± 13.7 years); 36% had disease duration of 10 years or more; rheumatoid factor (RF) and/or anticyclic citrullinated peptide (anti-CCP) were positive in 68%; and 17% had extra-articular manifestations. The EULAR multiplier factor was used in 122 (33%) of the patients. The mSCORE was 2.16 ± 2.49% and the mREGICOR 4.36 ± 3.46%. Regarding US results, 196 (53%) patients were US+. The AUC mSCORE was 0.798 (CI 95%: 0.752 to 0.844) and AUC mREGICOR 0.741 (95% CI; 0.691 to 0.792). However, mSCORE and mREGICOR failed to identify 88% and 91% of US+ patients. More than 50% of patients with mSCORE ≥1% or mREGICOR >1% were US+. Conclusions: Neither of these two function charts was useful in estimating CV risk in Spanish RA patients

African genomes illuminate the early history and transition to selfing in Arabidopsis thaliana

Over the past 20 y, many studies have examined the history of the plant ecological and molecular model, Arabidopsis thaliana, in Europe and North America. Although these studies informed us about the recent history of the species, the early history has remained elusive. In a large-scale genomic analysis of African A. thaliana, we sequenced the genomes of 78 modern and herbarium samples from Africa and analyzed these together with over 1,000 previously sequenced Eurasian samples. In striking contrast to expectations, we find that all African individuals sampled are native to this continent, including those from sub-Saharan Africa. Moreover, we show that Africa harbors the greatest variation and represents the deepest history in the A. thaliana lineage. Our results also reveal evidence that selfing, a major defining characteristic of the species, evolved in a single geographic region, best represented today within Africa. Demographic inference supports a model in which the ancestral A. thaliana population began to split by 120-90 kya, during the last interglacial and Abbassia pluvial, and Eurasian populations subsequently separated from one another at around 40 kya. This bears striking similarities to the patterns observed for diverse species, including humans, implying a key role for climatic events during interglacial and pluvial periods in shaping the histories and current distributions of a wide range of species.Peer Reviewe

Proyecto de un autobús urbano híbrido para el transporte de pasajeros

Se estima que en el año 2020 habrá más de 1.000 millones de vehículos en el mundo. Si todos estos vehículos fuesen equipados con motores de combustión interna convencionales, los niveles de contaminación serán inaceptables para el planeta (en las condiciones actuales). Basado en esto, han surgido en todo el mundo legislaciones que promueven, hasta exigen, el uso de “vehículos de emisión cero” (VECs) o no contaminantes. Hasta el momento, la única tecnología disponible, madura, para producir VECs es la de vehículos eléctricos (VEs). Debido a esto se estimó que para el año 2010 habría en el mercado mundial 1,5 millones de VEs. Actualmente, los vehículos eléctricos puros (VEPs) (los que no poseen generador a bordo) tienen dos grandes limitaciones: la baja densidad de energía de las baterías y la imposibilidad de recarga rápida de las mismas, lo que limita la autonomía de los VEPs. Este problema ha dado lugar a varias propuestas de Vehículos Eléctricos Híbridos (VEHs). El objetivo de nuestra propuesta fue desarrollar la tecnología y las partes necesarias para, finalmente, integrar un prototipo experimental de VEH para transporte urbano de pasajeros.Facultad de Ingenierí

Rv2577 of mycobacterium tuberculosis Is a virulence factor with dual phosphatase and phosphodiesterase functions

Tuberculosis, a lung disease caused by Mycobacterium tuberculosis (Mtb), is one of the ten leading causes of death worldwide affecting mainly developing countries. Mtb can persist and survive inside infected cells through modulation of host antibacterial attack, i.e., by avoiding the maturation of phagosome containing mycobacteria to more acidic endosomal compartment. In addition, bacterial phosphatases play a central role in the interplay between host cells and Mtb. In this study, we characterized the Rv2577 of Mtb as a potential alkaline phosphatase/phosphodiesterase enzyme. By an in vitro kinetic assay, we demonstrated that purified Rv2577 expressed in Mycobacterium smegmatis displays both enzyme activities, as evidenced by using the artificial substrates p-NPP and bis-(p-NPP). In addition, a three-dimensional model of Rv2577 allowed us to define the catalytic amino acid residues of the active site, which were confirmed by site-directed mutagenesis and enzyme activity analysis, being characteristic of a member of the metallophosphatase superfamily. Finally, a mutation introduced in Rv2577 reduced the replication of Mtb in mouse organs and impaired the arrest of phagosomes containing mycobacteria in early endosomes; which indicates Rv2577 plays a role in Mtb virulence

Rv2577 of Mycobacterium tuberculosis is a virulence factor with dual phosphatase and phosphodiesterase functions

Tuberculosis, a lung disease caused by Mycobacterium tuberculosis (Mtb), is one of the ten leading causes of death worldwide affecting mainly developing countries. Mtb can persist and survive inside infected cells through modulation of host antibacterial attack, i.e., by avoiding the maturation of phagosome containing mycobacteria to more acidic endosomal compartment. In addition, bacterial phosphatases play a central role in the interplay between host cells and Mtb. In this study, we characterized the Rv2577 of Mtb as a potential alkaline phosphatase/phosphodiesterase enzyme. By an in vitro kinetic assay, we demonstrated that purified Rv2577 expressed in Mycobacterium smegmatis displays both enzyme activities, as evidenced by using the artificial substrates p-NPP and bis-(p-NPP). In addition, a three-dimensional model of Rv2577 allowed us to define the catalytic amino acid residues of the active site, which were confirmed by site-directed mutagenesis and enzyme activity analysis, being characteristic of a member of the metallophosphatase superfamily. Finally, a mutation introduced in Rv2577 reduced the replication of Mtb in mouse organs and impaired the arrest of phagosomes containing mycobacteria in early endosomes; which indicates Rv2577 plays a role in Mtb virulence.Instituto de BiotecnologíaFil: Forrellad, Marina Andrea. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Agrobiotecnología y Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Blanco, Federico Carlos. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Agrobiotecnología y Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Marrero Diaz de Villegas, Rubén. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Agrobiotecnología y Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Vazquez, Cristina Lourdes. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Agrobiotecnología y Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Yaneff, Agustín. Universidad de Buenos Aires. Instituto de Investigaciones Farmacológicas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Garcia, Elizabeth Andrea. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Agrobiotecnología y Biología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Gutierrez, Maximiliano Gabriel. The Francis Crick Institute, Host-Pathogen Interactions in Tuberculosis Laboratory; Reino UnidoFil: Durán, Rosario. Institut Pasteur de Montevideo; Uruguay. Instituto de Investigaciones Biológicas Clemente Estable; UruguayFil: Villarino, Andrea. Universidad de la República (UdelaR). Facultad de Ciencias. Sección Bioquímica; UruguayFil: Bigi, Fabiana. Instituto Nacional de Tecnología Agropecuaria (INTA). Instituto de Agrobiotecnología y Biología Molecular; Argentina. Consejo Nacional de investigaciones Científicas y Tecnológicas; Argentin