Paracrine met signaling triggers epithelial mesenchymal transition in mammary luminal progenitors, affecting their fate

HGF/Met signaling has recently been associated with basal-type breast cancers, which are thought to originate from progenitor cells residing in the luminal compartment of the mammary epithelium. We found that ICAM-1 efficiently marks mammary luminal progenitors comprising hormone receptor-positive and receptor-negative cells, presumably ductal and alveolar progenitors. Both cell populations strongly express Met, while HGF is produced by stromal and basal myoepithelial cells. We show that persistent HGF treatment stimulates the clonogenic activity of ICAM1-positive luminal progenitors, controlling their survival and proliferation, and leads to the expression of basal cell characteristics, including stem cell potential. This is accompanied by the induction of Snai1 and Snai2, two major transcription factors triggering epithelial–mesenchymal transition, the repression of the luminal-regulatory genes Elf5 and Hey1, and claudin downregulation. Our data strongly indicate that paracrine Met signaling can control the function of luminal progenitors and modulate their fate during mammary development and tumorigenesis

Cause of Death and Predictors of All-Cause Mortality in Anticoagulated Patients With Nonvalvular Atrial Fibrillation : Data From ROCKET AF

M. Kaste on työryhmän ROCKET AF Steering Comm jäsen.Background-Atrial fibrillation is associated with higher mortality. Identification of causes of death and contemporary risk factors for all-cause mortality may guide interventions. Methods and Results-In the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF) study, patients with nonvalvular atrial fibrillation were randomized to rivaroxaban or dose-adjusted warfarin. Cox proportional hazards regression with backward elimination identified factors at randomization that were independently associated with all-cause mortality in the 14 171 participants in the intention-to-treat population. The median age was 73 years, and the mean CHADS(2) score was 3.5. Over 1.9 years of median follow-up, 1214 (8.6%) patients died. Kaplan-Meier mortality rates were 4.2% at 1 year and 8.9% at 2 years. The majority of classified deaths (1081) were cardiovascular (72%), whereas only 6% were nonhemorrhagic stroke or systemic embolism. No significant difference in all-cause mortality was observed between the rivaroxaban and warfarin arms (P=0.15). Heart failure (hazard ratio 1.51, 95% CI 1.33-1.70, P= 75 years (hazard ratio 1.69, 95% CI 1.51-1.90, P Conclusions-In a large population of patients anticoagulated for nonvalvular atrial fibrillation, approximate to 7 in 10 deaths were cardiovascular, whereasPeer reviewe

PATJ Low Frequency Variants Are Associated with Worse Ischemic Stroke Functional Outcome: A Genome-Wide Meta-Analysis

RATIONALE: Ischemic stroke is among the leading causes of adult disability. Part of the variability in functional outcome after stroke has been attributed to genetic factors but no locus has been consistently associated with stroke outcome. OBJECTIVE: Our aim was to identify genetic loci influencing the recovery process using accurate phenotyping to produce the largest GWAS (genome-wide association study) in ischemic stroke recovery to date. METHODS AND RESULTS: A 12-cohort, 2-phase (discovery-replication and joint) meta-analysis of GWAS included anterior-territory and previously independent ischemic stroke cases. Functional outcome was recorded using 3-month modified Rankin Scale. Analyses were adjusted for confounders such as discharge National Institutes of Health Stroke Scale. A gene-based burden test was performed. The discovery phase (n=1225) was followed by open (n=2482) and stringent joint-analyses (n=1791). Those cohorts with modified Rankin Scale recorded at time points other than 3-month or incomplete data on previous functional status were excluded in the stringent analyses. Novel variants in PATJ (Pals1-associated tight junction) gene were associated with worse functional outcome at 3-month after stroke. The top variant was rs76221407 (G allele, β=0.40, P=1.70×10-9). CONCLUSIONS: Our results identify a set of common variants in PATJ gene associated with 3-month functional outcome at genome-wide significance level. Future studies should examine the role of PATJ in stroke recovery and consider stringent phenotyping to enrich the information captured to unveil additional stroke outcome loci

Infection of novel reassortant H1N2 and H3N2 swine influenza A viruses in the guinea pig model

Novel H1N2 and H3N2 swine influenza A viruses (IAVs) were identified in commercial farms in Chile. These viruses contained H1, H3 and N2 sequences, genetically divergent from IAVs described worldwide, associated with pandemic internal genes. Guinea pigs were used as human surrogate to evaluate the infection dynamics of these reassortant viruses, compared with a pandemic H1N1 virus. All viruses replicated and were shed in the upper respiratory tract without prior adaptation although H1N2 viruses showed the highest shedding titers. This could have public health importance, emphasizing the need to carry out further studies to evaluate the zoonotic potential of these viruses

Exposure to tributyltin chloride induces penis and vas deferens development and increases RXR expression in females of the purple snail (Plicopurpura pansa)

Tributyltin (TBT) and its derivatives are widely used as antifouling paints for ships, resulting in their being released into the marine environment. Aquatic invertebrates, particularly marine gastropods, are extremely sensitive to TBT and undergo changes in the imposition of male secondary sex characteristics in response to exposure. This study aimed to evaluate the development of imposex and the expression of the retinoid X receptor (RXR) in tissues of Plicopurpura pansa (males and females) exposed to tributyltin chloride (TBTCl). The histological results showed a penis-like structure in imposexed female and an undeveloped vas deferens that lacked circular muscular layers. TBTCl treatment increased the messenger RNA (mRNA) of RXR in females with imposex. The highest level of mRNA RXR was found in the digestive gland and penis forming area in females under in vivo exposure compared with control females. These results indicate that TBTCl modulates mRNA levels of RXR in females. mRNA RXR in imposex females and females exposed to TBTCl only was similar to that of males, indicating that RXR might contribute to the development of imposex. To our knowledge, this study is the first to show that TBTCl induces imposex and biphallia in this snail species, and that this effect is accompanied by an increase in RXR expression.El tributilestaño (TBT) y sus derivados se utilizan ampliamente como pinturas antiincrustantes para buques, en el medio marino. Los invertebrados acuáticos, en particular los gasterópodos marinos, extremadamente sensibles a los TBT y sufren cambios en la imposición del sexo secundario masculino características en respuesta a la exposición. El presente estudio tuvo como objetivo evaluar el desarrollo de la expresión del receptor retinoide X (RXR) en tejidos de Plicopurpura pansa (machos y hembras) expuestos al cloruro de tributilestaño (TBTC1). Los resultados histológicos mostraron una estructura tipo pene en impuesta a la mujer y un vaso deferente no desarrollado que carecía de capas musculares circulares. TBTCl tratamiento aumentó el RNA mensajero (ARNm) de RXR en mujeres con imposex. El nivel más alto de ARNm RXR se encontró en la glándula digestiva y en el área de formación de pene en las mujeres bajo in vivo en comparación con las hembras control. Estos resultados indican que TBTCl modula los niveles de mRNA de RXR en mujeres. MRNA RXR en imposex hembras y las mujeres expuestas a TBTCl sólo fue similar a la de los machos, lo que indica que RXR podría contribuir al desarrollo de imposex. A nuestro conocimiento, este estudio es el primero en demostrar que TBTCl induce imposex y biphallia en esta especie de caracol, y que este efecto se acompaña de un aumento de la expresión de RXR

Deregulation of the humoral immune response of the oyster (Crassostrea corteziensis) exposed to naphthalene

Naphthalene is one of the most abundant polycyclic aromatic hydrocarbons (PAH) in aquatic ecosystems, and it can cause alterations in the immune system of organisms that live there. The oyster Crassostrea corteziensis is a species native to the Eastern Tropical Pacific, with economic and ecological importance. In this study, we evaluated the effect of subacute exposure to sublethal concentrations of naphthalene on the parameters of the humoral immune response (lysozyme and phenoloxidase activity, and nitric oxide production) on the oyster C. corteziensis. The results indicated that naphthalene, under the conditions tested, significantly deregulated the parameters evaluated. This could increase susceptibility to infections and therefore affect oyster production.El naftaleno es uno de los hidrocarburos aromáticos policíclicos más abundantes (HAP) en aguas ecosistemas, y puede causar alteraciones en el sistema inmunológico de los organismos que viven allí. Los Crassostrea corteziensis es una especie nativa del Pacífico oriental tropical, con características económicas e importancia ecológica. En este estudio, se evaluó el efecto de la exposición subaguda a sublethal concentraciones de naftaleno en los parámetros de la respuesta inmune humoral (lisozima y actividad fenoloxidasa y producción de óxido nítrico) en la ostra C. corteziensis. Los resultados indicados que el naftaleno, en las condiciones probadas, desreguló significativamente los parámetros evaluados. Esta podría aumentar la susceptibilidad a las infecciones y por lo tanto afectar la producción de ostras

Salting kinetics and salt diffusivities in farmed Pantanal caiman muscle Cinética de salga e difusividades de sal em carne de jacaré do Pantanal criado em cativeiro

The legal Pantanal caiman (Caiman crocodilus yacare) farming, in Brazil, has been stimulated and among meat preservation techniques the salting process is a relatively simple and low-cost method. The objective of this work was to study the sodium chloride diffusion kinetics in farmed caiman muscle during salting. Limited volumes of brine were employed, with salting essays carried at 3, 4 and 5 brine/muscle ratios, at 15%, 20% and 25% w/w brine concentrations, and brine temperatures of 10, 15 and 20ºC. The analytical solution of second Fick's law considering one-dimensional diffusion through an infinite slab in contact with a well-stirred solution of limited volume was used to calculate effective salt diffusion coefficients and to predict the sodium chloride content in the fillets. A good agreement was obtained between the considered analytical model and experimental data. Salt diffusivities in fillets were found to be in the range of 0.47x10-10 to 9.62x10-10 m²/s.<br>A criação de jacaré do Pantanal (Caiman crocodilus yacare) em cativeiro tem sido estimulada, e entre as técnicas de processamento de sua carne, a salga é um processo de conservação relativamente simples e de baixo custo. O objetivo deste trabalho foi estudar a cinética de difusão de cloreto de sódio em carne de jacaré do Pantanal criado em cativeiro, durante a salga úmida. Foram utilizados volumes limitados de salmoura e os experimentos foram realizados com relações salmoura/músculo de 3, 4 e 5, com concentrações de salmoura de 15%, 20% e 25% em peso e temperaturas de 10, 15 e 20ºC. A solução analítica da segunda lei de Fick, considerando difusão unidimensional em uma placa infinita em contato com uma solução bem agitada de volume limitado, foi utilizada para calcular os coeficientes de difusão efetivos de sal e estimar o conteúdo de cloreto de sódio nos filés. Obteve-se boa concordância entre o modelo analítico considerado e os dados experimentais. As difusividades do sal nos filés ocorreram na faixa de 0,47x10-10 a 9,62x10-10 m²/s