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Introduction: Phytotherapeutics, particularly extracts from Sabal serrulata (saw palmetto) fruit or Urtica dioica (stinging nettle) root, are popular for the treatment of male lower urinary symptoms in many countries, but their mechanism of action is poorly understood. We performed in vivo and in vitro studies to obtain deeper insight into the mechanism of action of WS® 1541, a proprietary combination of a Sabal serrulata fruit and an Urtica dioica root extract (WS® 1473 and WS® 1031, respectively) and its components. Methods: We used the sulpiride model of benign prostatic hyperplasia in rats and tested three doses of WS® 1541 in comparison to finasteride, evaluating weight of prostate and its individual lobes as well as aspects of inflammation, oxidative stress, growth and hyperplasia. In human BPH-1 cells, we studied the effect of WS® 1473, WS® 1031, WS® 1541 and finasteride on apoptosis, cell cycle progression and migrative capacity of the cells. Results: WS® 1541 did not reduce prostate size in sulpiride treated rats but attenuated the sulpiride-induced changes in expression of most analyzed genes and of oxidized proteins and abrogated the epithelial thickening. In vitro, WS® 1473 and WS® 1031 showed distinct profiles of favorable effects in BPH-1 cells including anti-oxidative, anti-proliferative and pro-apoptotic effects, as well as inhibiting epithelial-mesenchymal-transition. Conclusion: This data supports a beneficial effect of the clinically used WS® 1541 for the treatment of lower urinary tract symptoms associated with mild to moderate benign prostate syndrome and provides a scientific rationale for the combination of its components WS® 1473 and WS® 1031.

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In arteries and arterioles, a chronic increase in blood pressure raises wall tension. This continuous biomechanical strain causes a change in gene expression in vascular smooth muscle cells (VSMCs) that may lead to pathological changes. Here we have characterised the functional properties of lipoma-preferred partner (LPP), a Lin11-Isl1-Mec3 (LIM)-domain protein, which is most closely related to the mechanotransducer zyxin but selectively expressed by smooth muscle cells, including VSMCs in adult mice. VSMCs isolated from the aorta of LPP knockout (LPP-KO) mice displayed a higher rate of proliferation than their wildtype (WT) counterparts, and when cultured as three-dimensional spheroids, they revealed a higher expression of the proliferation marker Ki 67 and showed greater invasion into a collagen gel. Accordingly, the gelatinase activity was increased in LPP-KO but not WT spheroids. The LPP-KO spheroids adhering to the collagen gel responded with decreased contraction to potassium chloride. The relaxation response to caffeine and norepinephrine was also smaller in the LPP-KO spheroids than in their WT counterparts. The overexpression of zyxin in LPP-KO VSMCs resulted in a reversal to a more quiescent differentiated phenotype. In native VSMCs, i.e., in isolated perfused segments of the mesenteric artery (MA), the contractile responses of LPP-KO segments to potassium chloride, phenylephrine or endothelin-1 did not vary from those in isolated perfused WT segments. In contrast, the myogenic response of LPP-KO MA segments was significantly attenuated while zyxin-deficient MA segments displayed a normal myogenic response. We propose that LPP, which we found to be expressed solely in the medial layer of different arteries from adult mice, may play an important role in controlling the quiescent contractile phenotype of VSMCs.

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BACKGROUND: Robust and reliable in vitro and in vivo models of primary cells are necessary to study the pathomechanisms of Myelodysplastic Neoplasms (MDS) and identify novel therapeutic strategies. MDS-derived hematopoietic stem and progenitor cells (HSPCs) are reliant on the support of bone marrow (BM) derived mesenchymal stroma cells (MSCs). Therefore, isolation and expansion of MCSs are essential for successfully modeling this disease. For the clinical use of healthy MSCs isolated from human BM, umbilical cord blood or adipose tissue, several studies showed that xeno-free (XF) culture conditions resulted in superior growth kinetics compared to MSCs cultured in the presence of fetal bovine serum (FBS). In this present study, we investigate, whether the replacement of a commercially available MSC expansion medium containing FBS with a XF medium is beneficial for the expansion of MSCs derived from BM of MDS patients which are often difficult to cultivate. METHODS: MSCs isolated from BM of MDS patients were cultured and expanded in MSC expansion medium with FBS or XF supplement. Subsequently, the impact of culture media on growth kinetics, morphology, immunophenotype, clonogenic potential, differentiation capacity, gene expression profiles and ability to engraft in immunodeficient mouse models was evaluated. RESULTS: Significant higher cell numbers with an increase in clonogenic potential were observed during culture of MDS MSCs with XF medium compared to medium containing FBS. Differential gene expression showed an increase in transcripts associated with MSC stemness after expansion with XF. Furthermore, immunophenotypes of the MSCs and their ability to differentiate into osteoblasts, adipocytes or chondroblasts remained stable. MSCs expanded with XF media were similarly supportive for creating MDS xenografts in vivo as MSCs expanded with FBS. CONCLUSION: Our data indicate that with XF media, higher cell numbers of MDS MSCs can be obtained with overall improved characteristics in in vitro and in vivo experimental models.

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Limited response rates and frequent relapses during standard of care with hypomethylating agents in myelodysplastic neoplasms (MN) require urgent improvement of this treatment indication. Here, by combining 5-azacytidine (5-AZA) with the pan-lysyl oxidase inhibitor PXS-5505, we demonstrate superior restoration of erythroid differentiation in hematopoietic stem and progenitor cells (HSPCs) of MN patients in 20/31 cases (65%) versus 9/31 cases (29%) treated with 5-AZA alone. This effect requires direct contact of HSPCs with bone marrow stroma components and is dependent on integrin signaling. We further confirm these results in vivo using a bone marrow niche-dependent MN xenograft model in female NSG mice, in which we additionally demonstrate an enforced reduction of dominant clones as well as significant attenuation of disease expansion and normalization of spleen sizes. Overall, these results lay out a strong pre-clinical rationale for efficacy of combination treatment of 5-AZA with PXS-5505 especially for anemic MN.

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Arterial hypertension causes left ventricular hypertrophy leading to dilated cardiomyopathy. Following compensatory cardiomyocyte hypertrophy, cardiac dysfunction develops due to loss of cardiomyocytes preceded or paralleled by cardiac fibrosis. Zyxin acts as a mechanotransducer in vascular cells that may promote cardiomyocyte survival. Here, we analyzed cardiac function during experimental hypertension in zyxin knockout (KO) mice. In zyxin KO mice, made hypertensive by way of deoxycorticosterone acetate (DOCA)-salt treatment telemetry recording showed an attenuated rise in systolic blood pressure. Echocardiography indicated a systolic dysfunction, and isolated working heart measurements showed a decrease in systolic elastance. Hearts from hypertensive zyxin KO mice revealed increased apoptosis, fibrosis and an upregulation of active focal adhesion kinase as well as of integrins α5 and ß1. Both interstitial and perivascular fibrosis were even more pronounced in zyxin KO mice exposed to angiotensin II instead of DOCA-salt. Stretched microvascular endothelial cells may release collagen 1α2 and TGF-ß, which is characteristic for the transition to an intermediate mesenchymal phenotype, and thus spur the transformation of cardiac fibroblasts to myofibroblasts resulting in excessive scar tissue formation in the heart of hypertensive zyxin KO mice. While zyxin KO mice per se do not reveal a cardiac phenotype, this is unmasked upon induction of hypertension and owing to enhanced cardiomyocyte apoptosis and excessive fibrosis causes cardiac dysfunction. Zyxin may thus be important for the maintenance of cardiac function in spite of hypertension.

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Patient-derived xenograft (PDX) models have emerged as versatile preclinical platforms for investigation of functional pathomechanisms in myelodysplastic syndromes (MDS) and other myeloid neoplasms. However, despite increasingly improved methodology, engraftment efficiencies frequently remain low. Humanized three-dimensional scaffold models (ossicle xenotransplantation models) in immunocompromised mice have recently been found to enable improved engraftment rates of healthy and malignant human hematopoiesis. We therefore interrogated the feasibility of using four different three-dimensional ossicle-based PDX models for application with primary MDS samples. In a fully standardized comparison, we evaluated scaffold materials such as Gelfoam, extracellular matrix (ECM), and human or xenogenous bone substance in comparison to intrafemoral (IF) co-injection of bone marrow (BM)-derived mesenchymal stromal cells (MSCs) and CD34+ hematopoietic stem and progenitor cells (HSPCs). Our study included13 primary MDS patient samples transplanted in parallel according to these five different conditions. Engraftment of MDS samples was assessed by flow cytometry, immunohistological staining, and molecular validation. We determined that three-dimensional ossicle-based methods achieved higher relative rates of engraftment and enabled long-term retrievability of patient-derived MSCs from implanted ossicles. In summary, HSPCs and MSCs derived from MDS BM, which did not significantly engraft in NSG mice after intrafemoral injection, were able to colonize humanized scaffold models. Therefore, these models are promising new xenotransplantation techniques for addressing preclinical and functional questions of the interaction between hematopoiesis and the BM niche in MDS.

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Resumo Neste artigo, objetivou-se analisar a forma como os governos municipais responderam à crise sanitária e quais medidas desenvolveram em termos de diagnóstico da Covid-19 e alocação dos recursos provenientes de fontes federais. Para tanto, informações oriundas de uma pesquisa com 4.061 prefeitos coordenada pela Confederação Nacional dos Municípios foram sistematizadas e comparadas com outras bases de dados oficiais. Conclui-se que, a despeito da falta de instrumentos de coordenação desenvolvidos em âmbito federal, a destinação dos recursos e o desenvolvimento de políticas por parte dos municípios se orientaram pela concentração de serviços de referência regional em municípios de grande e médio portes.

Abstract This article aimed to analyze how municipal governments responded to the health crisis and what measures they developed in terms of diagnosing Covid-19 and allocating resources from Brazil's federal sources. To this end, information from a survey with 4,061 mayors coordinated by the National Confederation of Municipalities was systematized and compared with other official databases. We concluded that, despite the lack of coordination instruments developed at the federal level, the allocation of resources and the development of policies by the municipalities were guided by the concentration of regional reference services in large and medium-sized municipalities.

Resumen El trabajo tiene como objetivo analizar cómo los gobiernos municipales respondieron a la crisis sanitaria, qué medidas desarrollaron en términos de diagnóstico de Covid-19 y cómo asignaron los recursos transferidos desde el gobierno federal de Brasil. Para ello, se sistematizó la información de una encuesta coordinada por la Confederación Nacional de Municipios y se comparó con otras bases de datos oficiales. En cuanto a la conclusión, se argumenta que, a pesar de la falta de instrumentos de coordinación desarrollados a nivel federal, la asignación de recursos y el desarrollo de políticas por parte de los municipios estuvieron orientados por la concentración de los servicios regionales de referencia en los municipios grandes y medianos.

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Resumo O artigo teve como objetivo investigar de que modo os municípios brasileiros desenvolveram medidas para enfrentar a pandemia de Covid-19. Para isso, foi conduzido um estudo com dados da Confederação Nacional dos Municípios, coletados no segundo semestre de 2020. Os resultados apontaram que houve, inicialmente, a adoção de medidas como a implementação de barreiras sanitárias, isolamento social e promoção do uso de máscara; contudo, a maioria dos municípios flexibilizou essas ações ao longo do tempo. Além disso, observou-se que os entes municipais desenvolveram ações de resposta à pandemia de forma heterogênea e descoordenada. Concluiu-se que esse fenômeno se deve ao fato de que o governo federal e os estados da federação desenvolveram precários mecanismos de incentivo à cooperação interfederativa e pouco estimularam a coordenação de atividades no território brasileiro.

Abstract The article aimed to investigate how Brazilian municipalities developed measures to face the COVID-19 pandemic. To this end, a survey was conducted with data from the National Confederation of Municipalities collected in the second semester of 2020. The results showed that measures were initially adopted, such as the implementation of sanitary barriers, social isolation and the rise of the mask use; however, most municipalities have made these actions more flexible over time. In addition, it was observed that municipal entities developed actions to respond to the pandemic in a heterogeneous and uncoordinated way. It is concluded that this phenomenon is due to the fact that the federal government and the states of the federation developed precarious mechanisms to encourage inter-federative cooperation and little stimulated the coordination of activities in order to guarantee uniformity of the actions developed in the Brazilian territory.

Resumen El artículo tuvo como objetivo investigar cómo los municipios brasileños han desarrollado medidas para hacer frente a la pandemia de Covid-19. Para ello, se ha realizado un estudio con datos de la Confederación Nacional de Municipios en el segundo semestre de 2020. Los resultados indicaron que, inicialmente, se adoptaron medidas como la implantación de barreras sanitarias, el aislamiento social y la promoción del uso de mascarillas; sin embargo, la mayoría de los municipios relajaron estas acciones con el tiempo. Además, se observó que los municipios desarrollan acciones de respuesta a la pandemia de forma heterogénea y desordenada. Se concluyó que ese fenómeno se debe a que el gobierno federal y los estados de la federación desarrollaron mecanismos precarios para incentivar la cooperación interfederativa e hicieron poco para estimular la coordinación de actividades para garantizar la uniformidad de las acciones desarrolladas en el territorio brasileño.

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O artigo busca compreender práticas psicológicas no ano da regulamentação da psicologia no Brasil. A pesquisa se baseia em matérias sobre as relações políticas, o comportamento cotidiano e a divulgação científica do jornal Correio do Povo. A coleta ocorreu no Museu de Comunicação Hipólito José da Costa, em Porto Alegre onde foi feita a seleção e fotografia de materiais referentes à psicologia. Posteriormente, foi criado um banco de dados para análise temática e discussão do material. Dentre os resultados sobressaíram-se algumas estratégias voltadas para a legitimação da área como a inserção na mídia impressa com a divulgação de cursos, pesquisas, debates e aconselhamentos. Foram evidentes as correspondências entre as práticas psicológicas explicitadas no Jornal e o contexto sócio político da época pautado pela ênfase no desenvolvimento econômico e tecnológico, pela evitação de conflitos e pela crença de que a ciência psicológica poderia promover a humanização das relações.(AU)

This research paper aims to understand the psychological practices in 1962, the year of formalization of Psychology in Brazil. The research is based on contents about political relations, behavior and science popularization in the newspaper "Correio do Povo". Data were collected at Hipólito José da Costa Museum of Communication in Porto Alegre where all material related to psychology was selected and photographed. Afterwards, a database for analysis and material discussion was created. Among the results, some strategies oriented to the field's legitimation stood out, as the insertion in the print media with the promotion of courses, researches, debates and advices. There was an evident correspondence between the psychological practices explained in the newspaper and the socio-political context guided by the economical and technological development emphasis, by the conflict avoidance and by the belief in the psychological science as a promoter of humanization in relationships.(AU)

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