48 research outputs found
Thereâs no truth-theory like the correspondence theory.
Este artĂculo desafĂa la suposiciĂłn de que las teorĂas de la verdad pragmatistas, coherentistas, de la identidad y deflacionarias constituyen perspectivas rivales de y son esencialmente incompatibles con la teorĂa correspondentista, sin asumir el pluralismo. Con excepciĂłn de cierta versiĂłn de la teorĂa identitaria de la verdad, las teorĂas alternativas solo parecen contradecir de manera genuina a la teorĂa correspondentista, o bien cuando estĂĄn unidas al rechazo de una realidad objetiva, o cuando se asume que una âteorĂa de la verdadâ es una teorĂa de la funciĂłn del predicado âverdaderoâ. Argumento que la teorĂa correspondentista no debe entenderse como una teorĂa acerca de la funciĂłn del predicado âverdaderoâ, y que las ideas centrales de las perspectivas alternativas, una vez se separan de algunas convicciones anti-realistas, se comprenden mejor como perspectivas complementarias sobre diferentes aspectos de un fenĂłmeno muy complejo; a saber, el de cĂłmo nuestras creencias se relacionan con sus objetos y el de cĂłmo razonamos y hablamos sobre esa relaciĂłn.I challenge the assumption that pragmatist, coherence, identity, and deflationary theories of truth are essentially rival views to the correspondence theory, but I do not endorse pluralism. Except for some versions of the identity theory, the alternative theories only seem to genuinely contradict the correspondence theory, either when they are combined with a rejection of an objective reality or when it is assumed that to offer a âtheory of truthâ is to offer a theory of the function of the truthpredicate. I argue that the correspondence theory should not be understood as a theory about the function of the truthpredicate, and that the core ideas of the alternative views, once separated from any anti-realist convictions, are best understood as complementary views about different aspects of a fairly complex phenomenon, notably of how our beliefs relate to their subject matter and how we reason and talk about that relation
The Metaphysics of Relations, by Anna Marmodoro and David Yates
info:eu-repo/semantics/publishedVersio
Causal Efficacy: A Comparison of Rival Views
The idea that causation involves the production of changes due to the exertion of influence of something on something elseâthe core idea of causal realismâused to be the default view. Today this idea is at the heart of (i) transmission/causal process accounts, (ii) mechanistic accounts, and (iii) powers-based accounts. However, as I have previously argued (Ingthorsson 2021) the above-mentioned approaches are basedâto varying degreeâon the very problematic assumption that causal influence is essentially unidirectional; that it passes from whatever is the cause to the effect. As first pointed out be Mario Bunge (1959), the idea that causal influence is unidirectional is incompatible with what is today considered a scientific fact, notably that all interactions are perfectly reciprocal; whenever any object exerts an influence on any other object, the latter simultaneously exerts the same kind of influence, of the same magnitude, on the former. Drawing on Bungeâs result, I have developed a fourth approach to efficient causation that accepts the reciprocity of interactions (Ingthorsson 2002 & 2021). According to this view a cause is not the action of something on something else that receives the influence, but the reciprocal action between powerful particulars which results in a modification of both sides, producing a new state of affairs. In this paper, I present the core ideas of the four different approaches to causal efficacy, what I think is problematic with the first three and finally attempt to compare how well the four approaches fare in explaining two often discussed types of causal interactions: (i) collisions between billiard balls, and (ii) how water dissolves salt. I argue that only reciprocal actions between powerful particulars can plausibly claim to fully account for these phenomena, in a manner compatible with the theories and findings of the natural sciences
Naturvetenskap vs. Humanvetenskap: Myt, Metodologi och Ontologi
Jag tror att det Ă€r ett misstag att krĂ€va av humanvetenskaperna (d.v.s. humaniora, samhĂ€lls- och beteendevetenskaperna) att de imiterar naturvetenskapernas forskningsmetodik. Humanvetenskaperna studerar meningsfulla fenomen vilkas natur Ă€r pĂ„ ett grundlĂ€ggande sĂ€tt annorlunda Ă€n de blott fysiska fenomen som naturvetenskapen studerar. Den största skillnaden Ă€r att meningsfulla fenomen inte uppenbarligen Ă€r lagbundna pĂ„ samma sĂ€tt som fysiska fenomen och uppvisar dĂ€rför inte samma regelbundenhet och förutsĂ€gbarhet som fysiska fenomen. För att studera meningsfulla fenomen krĂ€vs dĂ€rför andra forskningsmetoder. Trots att humanvetenskaperna studerar fenomen som inte Ă€r lagbundna och Ă€r pĂ„ ett visst sĂ€tt subjektiva, sĂ„ vill jag mena att de studerar objektivt verkliga fenomen och kan fĂ„ giltig kunskap om dem. Att subjektiva fenomen ocksĂ„ kan vara objektivt verkliga kan lĂ„ta mĂ€rkligt för vissa lĂ€sare, varför jag rundar av med en diskussion om vad det egentligen innebĂ€r för nĂ„got att vara objektivt verkligt. Enligt den definition jag föreslĂ„r sĂ„ framstĂ„r att meningsfulla fenomen, ocksĂ„ de som kallas âsociala konstruktionerâ, kan förstĂ„s som objektivt verkliga företeelser trots att de pĂ„ ett betydelsefullt sĂ€tt ocksĂ„ Ă€r subjektiva
Mario Bunge and the Current Revival of Causal Realism
Mario Bungeâs Causality and Modern Science is arguably one of the best treatments of the causal realist tradition ever to have been written, one that defends the place of causality as a category in the conceptual framework of modern science. And yet in the current revival of causal realism in contemporary metaphysics, there is very little awareness of Bungeâs work. This paper seeks to remedy this, by highlighting one particular criticism Bunge levels at the Aristotelian view of causation and illustrating its relevance for contemporary powers-based accounts. Roughly, the Aristotelian view depicts interactions between objects as involving a unidirectional exertion of influence of one object upon another. This idea of unidirectional action is central to the Aristotelian distinction between active and passive powers, and its corresponding distinction between active and passive objects. As Bunge points out, modern physics does not recognise the existence of any unidirectional actions at all; all influence comes in the form of reciprocal action, or interaction. If this is right, all notions deriving from or influenced by the idea of unidirectional actionsâsuch as the concept of mutual manifestation and reciprocal disposition partnersârisk being false by the same measure. Bunge drew the conclusion that the Aristotelian view is ontologically inadequate, but still advocated its use as the most useful approximation available in science. He considered, but ultimately rejected the possibility of a modified view of causation built on reciprocal action, because, in his view, it couldnât account for the productivity of causation. Bungeâs critique of this particular aspect of the Aristotelian view cannot be overlooked in contemporary metaphysics, but it is possible to construe a modified view of causation that takes the reciprocity of interactions seriously without loss of productivity.Peer reviewe
HER2 induced EMT and tumorigenicity in breast epithelial progenitor cells is inhibited by coexpression of EGFR.
To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked Files.
This article is open access.The members of the epidermal growth factor receptor (EGFR) kinase family are important players in breast morphogenesis and cancer. EGFR2/HER2 and EGFR expression have a prognostic value in certain subtypes of breast cancer such as HER2-amplified, basal-like and luminal type B. Many clinically approved small molecular inhibitors and monoclonal antibodies have been designed to target HER2, EGFR or both. There is, however, still limited knowledge on how the two receptors are expressed in normal breast epithelium, what effects they have on cellular differentiation and how they participate in neoplastic transformation. D492 is a breast epithelial cell line with stem cell properties that can undergo epithelial to mesenchyme transition (EMT), generate luminal- and myoepithelial cells and form complex branching structures in three-dimensional (3D) culture. Here, we show that overexpression of HER2 in D492 (D492(HER2)) resulted in EMT, loss of contact growth inhibition and increased oncogenic potential in vivo. HER2 overexpression, furthermore, inhibited endogenous EGFR expression. Re-introducing EGFR in D492(HER2) (D492(HER2/EGFR)) partially reversed the mesenchymal state of the cells, as an epithelial phenotype reappeared both in 3D cultures and in vivo. The D492(HER2/EGFR) xenografts grow slower than the D492(HER2) tumors, while overexpression of EGFR alone (D492(EGFR)) was not oncogenic in vivo. Consistent with the EGFR-mediated epithelial phenotype, overexpression of EGFR drove the cells toward a myoepithelial phenotype in 3D culture. The effect of two clinically approved anti-HER2 and EGFR therapies, trastuzumab and cetuximab, was tested alone and in combination on D492(HER2) xenografts. While trastuzumab had a growth inhibitory effect compared with untreated control, the effect of cetuximab was limited. When administered in combination, the growth inhibitory effect of trastuzumab was less pronounced. Collectively, our data indicate that in HER2-overexpressing D492 cells, EGFR can behave as a tumor suppressor, by pushing the cells towards epithelial differentiation.Landspitali University Hospital Science Fund,
University of Iceland Research Fund, Science and Technology Policy Council Research
Fund and Grant of Excellence, âGöngum samanâ, a supporting group for breast cancer
research in Iceland
Azithromycin induces epidermal differentiation and multivesicular bodies in airway epithelia.
To access publisher's full text version of this article, please click on the hyperlink in Additional Links field or click on the hyperlink at the top of the page marked DownloadBACKGROUND:
Azithromycin (Azm) is a macrolide recognized for its disease-modifying effects and reduction in exacerbation of chronic airway diseases. It is not clear whether the beneficial effects of Azm are due to its anti-microbial activity or other pharmacological actions. We have shown that Azm affects the integrity of the bronchial epithelial barrier measured by increased transepithelial electrical resistance. To better understand these effects of Azm on bronchial epithelia we have investigated global changes in gene expression.
METHODS:
VA10 bronchial epithelial cells were treated with Azm and cultivated in air-liquid interface conditions for up to 22âdays. RNA was isolated at days 4, 10 and 22 and analyzed using high-throughput RNA sequencing. qPCR and immunostaining were used to confirm key findings from bioinformatic analyses. Detailed assessment of cellular changes was done using microscopy, followed by characterization of the lipidomic profiles of the multivesicular bodies present.
RESULTS:
Bioinformatic analysis revealed that after 10âdays of treatment genes encoding effectors of sterol and cholesterol metabolism were prominent. Interestingly, expression of genes associated with epidermal barrier differentiation, KRT1, CRNN, SPINK5 and DSG1, increased significantly at day 22. Together with immunostaining, these results suggest an epidermal differentiation pattern. We also found that Azm induced the formation of multivesicular and lamellar bodies in two different airway epithelial cell lines. Lipidomic analysis revealed that Azm was entrapped in multivesicular bodies linked to different types of lipids, most notably palmitate and stearate. Furthermore, targeted analysis of lipid species showed accumulation of phosphatidylcholines, as well as ceramide derivatives.
CONCLUSIONS:
Taken together, we demonstrate how Azm might confer its barrier enhancing effects, via activation of epidermal characteristics and changes to intracellular lipid dynamics. These effects of Azm could explain the unexpected clinical benefit observed during Azm-treatment of patients with various lung diseases affecting barrier function.Icelandic Research Council
EpiEndo Pharmaceuticals, Reykjavik, Icelan
Recapitulation of tumor heterogeneity and molecular signatures in a 3D brain cancer model with decreased sensitivity to histone deacetylase inhibition
INTRODUCTION
Physiologically relevant pre-clinical ex vivo models recapitulating CNS tumor micro-environmental complexity will aid development of biologically-targeted agents. We present comprehensive characterization of tumor aggregates generated using the 3D Rotary Cell Culture System (RCCS).
METHODS
CNS cancer cell lines were grown in conventional 2D cultures and the RCCS and comparison with a cohort of 53 pediatric high grade gliomas conducted by genome wide gene expression and microRNA arrays, coupled with immunohistochemistry, ex vivo magnetic resonance spectroscopy and drug sensitivity evaluation using the histone deacetylase inhibitor, Vorinostat.
RESULTS
Macroscopic RCCS aggregates recapitulated the heterogeneous morphology of brain tumors with a distinct proliferating rim, necrotic core and oxygen tension gradient. Gene expression and microRNA analyses revealed significant differences with 3D expression intermediate to 2D cultures and primary brain tumors. Metabolic profiling revealed differential profiles, with an increase in tumor specific metabolites in 3D. To evaluate the potential of the RCCS as a drug testing tool, we determined the efficacy of Vorinostat against aggregates of U87 and KNS42 glioblastoma cells. Both lines demonstrated markedly reduced sensitivity when assaying in 3D culture conditions compared to classical 2D drug screen approaches.
CONCLUSIONS
Our comprehensive characterization demonstrates that 3D RCCS culture of high grade brain tumor cells has profound effects on the genetic, epigenetic and metabolic profiles of cultured cells, with these cells residing as an intermediate phenotype between that of 2D cultures and primary tumors. There is a discrepancy between 2D culture and tumor molecular profiles, and RCCS partially re-capitulates tissue specific features, allowing drug testing in a more relevant ex vivo system