Selective glucocorticoid receptor-activating adjuvant therapy in cancer treatments

Although adverse effects and glucocorticoid resistance cripple their chronic use, glucocorticoids form the mainstay therapy for acute and chronic inflammatory disorders, and play an important role in treatment protocols of both lymphoid malignancies and as adjuvant to stimulate therapy tolerability in various solid tumors. Glucocorticoid binding to their designate glucocorticoid receptor (GR), sets off a plethora of cell-specific events including therapeutically desirable effects, such as cell death, as well as undesirable effects, including chemotherapy resistance, systemic side effects and glucocorticoid resistance. In this context, selective GR agonists and modulators (SEGRAMs) with a more restricted GR activity profile have been developed, holding promise for further clinical development in anti-inflammatory and potentially in cancer therapies. Thus far, the research into the prospective benefits of selective GR modulators in cancer therapy limped behind. Our review discusses how selective GR agonists and modulators could improve the therapy regimens for lymphoid malignancies, prostate or breast cancer. We summarize our current knowledge and look forward to where the field should move to in the future. Altogether, our review clarifies novel therapeutic perspectives in cancer modulation via selective GR targeting

Effect of combining glucocorticoids with Compound A on glucocorticoid receptor responsiveness in lymphoid malignancies

Glucocorticoids (GCs) are a cornerstone in the treatment of lymphoid malignancies such as multiple myeloma (MM) and acute lymphoblastic leukemia (ALL). Yet, prolonged GC use is hampered by deleterious GC-related side effects and the emergence of GC resistance. To tackle and overcome these GC-related problems, the applicability of selective glucocorticoid receptor agonists and modulators was studied, in search of fewer side-effects and at least equal therapeutic efficacy as classic GCs. Compound A (CpdA) is a prototypical example of such a selective glucocorticoid receptor modulator and does not support GR-mediated transactivation. Here, we examined whether the combination of CpdA with the classic GC dexamethasone (Dex) may improve GC responsiveness of MM and ALL cell lines. We find that the combination of Dex and CpdA does not substantially enhance GC-mediated cell killing. In line, several apoptosis hallmarks, such as caspase 3/7 activity, PARP cleavage and the levels of cleaved-caspase 3 remain unchanged upon combining Dex with CpdA. Moreover, we monitor no additional inhibition of cell proliferation and the homologous downregulation of GR is not counteracted by the combination of Dex and CpdA. In addition, CpdA is unable to modulate Dex-liganded GR transactivation and transrepression, yet, Dex-mediated transrepression is also aberrant in these lymphoid cell lines. Together, transrepression-favoring compounds, alone or combined with GCs, do not seem a valid strategy in the treatment of lymphoid malignancies

Academia Meets Practice

Based on examples of antifeminist and anti-»genderist« attacks against scholars in Women’s, Gender and Feminist Studies (WGFS) as well as practitioners and activists, this paper proposes relevant counterstrategies. After briefly outlining the characteristics of current antifeminist and anti-»genderist« discourses, we share our own experiences with such attacks. We discuss criticisms of and defamations against WGFS inside academia, antifeminist interventions in journalistic public spheres and difficulties encountered in collaborations between WGFS scholars and activists. From our experiences, we derive seven suggestions for strategies which WGFS could utilize to counter these attacks in a transdisciplinary, intersectional way.Anhand von Beispielen antifeministischer und anti-"genderistischer" Angriffe auf Wissenschaftler*innen der Frauen-, Geschlechter- und Feminismusforschung (Women’s, Gender and Feminist Studies, WGFS), Aktivist*innen und in der Praxis tätige Personen schlagen wir in diesem Beitrag entsprechende Gegenstrategien vor. Nach einem kurzen Überblick über die Merkmale aktueller antifeministischer und anti-"genderistischer" Diskurse berichten wir über unsere eigenen Erfahrungen mit solchen Angriffen und erörtern Kritik an und Diffamierungen von WGFS innerhalb der scientific community, antifeministische Interventionen in der journalistischen Öffentlichkeit und Herausforderungen in der Zusammenarbeit zwischen WGFS-Wissenschaftler*innen und -Aktivist*innen. Aus unseren Erfahrungen leiten wir sieben Vorschläge für Strategien ab, die WGFS nutzen könnten, um diesen Angriffen auf transdisziplinäre, intersektionale Weise zu begegnen.Peer Reviewe

Aerosolizable marine phycotoxins and human health effects : in vitro support for the biogenics hypothesis

Respiratory exposure to marine phycotoxins is of increasing concern. Inhalation of sea spray aerosols (SSAs), during harmful Karenia brevis and Ostreopsis ovata blooms induces respiratory distress among others. The biogenics hypothesis, however, suggests that regular airborne exposure to natural products is health promoting via a downregulation of the mechanistic target of rapamycin (mTOR) pathway. Until now, little scientific evidence supported this hypothesis. The current explorative in vitro study investigated both health-affecting and potential health-promoting mechanisms of airborne phycotoxin exposure, by analyzing cell viability effects via cytotoxicity assays and effects on the mTOR pathway via western blotting. To that end, A549 and BEAS-2B lung cells were exposed to increasing concentrations (ng·L−1 – mg·L−1) of (1) pure phycotoxins and (2) an extract of experimental aerosolized homoyessotoxin (hYTX). The lowest cell viability effect concentrations were found for the examined yessotoxins (YTXs). Contradictory to the other phycotoxins, these YTXs only induced a partial cell viability decrease at the highest test concentrations. Growth inhibition and apoptosis, both linked to mTOR pathway activity, may explain these effects, as both YTXs were shown to downregulate this pathway. This proof-of-principle study supports the biogenics hypothesis, as specific aerosolizable marine products (e.g., YTXs) can downregulate the mTOR pathway

FOLGA ORGANIZACIONAL: ANÁLISE EM UMA PERSPECTIVA COMPORTAMENTAL NO CAMPO EMPÍRICO

Este estudo objetiva verificar como se apresenta a folga organizacional no campo empírico. Diferente das proposições observadas na literatura de identificar medidas para calcular a folga organizacional, esta investigação concentra-se nas características predominantemente subjetivas da folga, visando ao entendimento deste conceito sob a perspectiva comportamental. Assim, pesquisa indutiva e exploratória, com abordagem qualitativa, foi realizada a partir de um estudo de caso em uma empresa do setor têxtil. As categorias de folga organizacional foram extraídas da literatura e consubstanciadas em um roteiro de entrevista, aplicado a sete diretores/gerentes da empresa. As entrevistas foram analisadas por meio da técnica de análise de conteúdo e trianguladas com fontes documentais e de mídias. Os resultados da pesquisa denotam presença de folga organizacional nas perspectivas de recursos (humanos, físicos e financeiros), tempo e poder. Contudo, o construto desenvolvido para aferir a presença da folga organizacional não investigou as motivações, o que indica uma lacuna de pesquisa

Mechanisms underlying the functional cooperation between PPARα and GRα to attenuate inflammatory responses

Glucocorticoids (GCs) act via the glucocorticoid receptor (NR3C1, GR alpha) to combat overshooting responses to infectious stimuli, including lipopolysaccharide (LPS). As such, GCs inhibit the activity of downstream effector cytokines, such as tumor necrosis factor (TNF). PPAR alpha (NR1C1) is a nuclear receptor described to function on the crossroad between lipid metabolism and control of inflammation. In the current work, we have investigated the molecular mechanism by which GCs and PPAR alpha agonists cooperate to jointly inhibit NF-kappa B-driven expression in A549 cells. We discovered a nuclear mechanism that predominantly targets Mitogen- and Stress-activated protein Kinase-1 activation upon co-triggering GR alpha and PPAR alpha. In vitro GST-pull down data further support that the anti-inflammatory mechanism may additionally involve a non-competitive physical interaction between the p65 subunit of NF-kappa B, GR alpha, and PPAR alpha. Finally, to study metabolic effector target cells common to both receptors, we overlaid the effect of GR alpha and PPAR alpha crosstalk in mouse primary hepatocytes under LPS-induced inflammatory conditions on a genome-wide level. RNA-seq results revealed lipid metabolism genes that were upregulated and inflammatory genes that were additively downregulated. Validation at the cytokine protein level finally supported a consistent additive anti-inflammatory response in hepatocytes

Selective glucocorticoid receptor modulation: New directions with non-steroidal scaffolds

AbstractGlucocorticoids remain the frontline treatment for inflammatory disorders, yet represent a double-edged sword with beneficial therapeutic actions alongside adverse effects, mainly in metabolic regulation. Considerable efforts were made to improve this balance by attempting to amplify therapeutic beneficial anti-inflammatory actions and to minimize adverse metabolic actions. Most attention has focused on the development of novel compounds favoring the transrepressing actions of the glucocorticoid receptor, assumed to be important for anti-inflammatory actions, over the transactivating actions, assumed to underpin the undesirable actions. These compounds are classified as selective glucocorticoid receptor agonists (SEGRAs) or selective glucocorticoid receptor modulators (SEGRMs). The latter class is able to modulate the activity of a GR agonist and/or may not classically bind the glucocorticoid receptor ligand-binding pocket. SEGRAs and SEGRMs are collectively denominated SEGRAMs (selective glucocorticoid receptor agonists and modulators). Although this transrepression vs transactivation concept proved to be too simplistic, the developed SEGRAMs were helpful in elucidating various molecular actions of the glucocorticoid receptor, but have also raised many novel questions.We discuss lessons learned from recent mechanistic studies of selective glucocorticoid receptor modulators. This is approached by analyzing recent experimental insights in comparison with knowledge obtained using mutant GR research, thus clarifying the current view on the SEGRAM field. These insights also contribute to our understanding of the processes controlling glucocorticoid-mediated side effects as well as glucocorticoid resistance. Our perspective on non-steroidal SEGRAs and SEGRMs considers remaining opportunities to address research gaps in order to harness the potential for more safe and effective glucocorticoid receptor therapies

Do Shared Interests Affect the Accuracy of Budgets?

A criação da folga orçamentária é um fenômeno associado com diferentes aspectos comportamentais, mas neste estudo se destaca o que focaliza a veracidade na elaboração dos orçamentos quando o benefício da folga é compartilhado entre o gerente da unidade e seu assistente. Neste caso, a veracidade é mensurada pelo nível de folga nos orçamentos e o benefício da folga representa um reflexo financeiro para o gerente e seu assistente. O estudo objetiva verificar como os interesses compartilhados na folga orçamentária afetam a veracidade dos relatórios orçamentários em uma organização. Para tal, realizou-se pesquisa experimental com uma amostra de 90 empregados, em cargos de gerência e liderança, de uma cooperativa que possui um plano de remuneração variável baseado no alcance das metas organizacionais. O experimento realizado na pesquisa consubstanciou-se no estudo de Church, Hannan, e Kuang (2012), desenvolvido com alunos de ensino superior dos Estados Unidos, e utilizou abordagem quantitativa na análise dos resultados. Constatou-se na primeira parte do experimento que, na condição de não compartilhamento da folga, os gerentes tendem a criar maior folga quando o seu assistente não é conhecedor da situação, refletindo-se em um índice de veracidade inferior, quando comparado com o assistente conhecedor da situação. Na condição de compartilhamento da folga, constatou-se média superior de folga quando o assistente é conhecedor da situação. Na segunda parte do experimento, os gerentes apontaram maior índice de veracidade na situação em que elaboram seu orçamento sabendo que seu assistente tem preferência por valores maiores de folga. Porém, o nível de veracidade é diferente entre os gerentes que sabem que o assistente prefere maximização de valores e gerentes que não sabem a preferência do assistente. Esses resultados contribuem com a literatura, ao apresentar evidências do comportamento de gerentes na criação de folga orçamentária em cenários de compartilhamento dos benefícios da folga com seus assistentes.The creation of budgetary slack is a phenomenon associated with various behavioral aspects. This study focuses on accuracy in budgeting when the benefit of the slack is shared between the unit manager and his/her assistant. In this study, accuracy is measured by the level of slack in the budget, and the benefit of slack represents a financial consideration for the manager and the assistant. The study aims to test how shared interests in budgetary slack affect the accuracy of budget reports in an organization. To this end, an experimental study was conducted with a sample of 90 employees in management and other leadership positions at a cooperative that has a variable compensation plan based on the achievement of organizational goals. The experiment conducted in this study is consubstantiated by the study of Church, Hannan and Kuang (2012), which was conducted with a sample of undergraduate students in the United States and used a quantitative approach to analyze the results. In the first part of the experiment, the results show that when budgetary slack is not shared, managers tend to create greater slack when the assistant is not aware of the creation of slack; these managers thus generate a lower accuracy index than managers whose assistants are aware of the creation of slack. When budgetary slack is shared, there is higher average slack when the assistant is aware of the creation of slack. In the second part of the experiment, the accuracy index is higher for managers who prepare the budget with the knowledge that their assistants prefer larger slack values. However, the accuracy level differs between managers who know that their assistants prefer maximizing slack values and managers who do not know their assistants' preference regarding slack. These results contribute to the literature by presenting evidence of managers' behavior in the creation of budgetary slack in scenarios in which they share the benefits of slack with their assistants