Regulation of cell migration in cancer: investigation into the regulation of cancer cell blebbing in the extracellular matrix

Cell migration is a highly coordinated process and any aberration in the regulatory mechanisms could result in pathological conditions such as cancer. The ability of cancer cells to disseminate to distant sites within the body has made it difficult to treat. Cancer cells also exhibit plasticity that makes them able to interconvert from an elongated, mesenchymal morphology to an amoeboid blebbing form under different physiological conditions. Blebs are spherical membrane protrusions formed by actomyosin-mediated contractility of cortical actin resulting in increased hydrostatic pressure and subsequent detachment of the membrane from the cortex. Tumour cells use blebbing as an alternative mode of migration by squeezing through preexisting gaps in the ECM, and bleb formation is believed to be mediated by the Rho-ROCK signaling pathway. However, the involvement of transmembrane water and ion channels in cell blebbing has not been examined. In the present study, the role of the transmembrane water channels, aquaporins, transmembrane ion transporters and lipid signaling enzymes in the regulation of blebbing was investigated. Using 3D matrigel matrix as an in vitro model to mimic normal extracellular matrix, and a combination of confocal and time-lapse microscopy, it was found that AQP1 knockdown by siRNA ablated blebbing of HT1080 and ACHN cells, and overexpression of AQP1-GFP not only significantly increased bleb size with a corresponding decrease in bleb numbers, but also induced bleb formation in non-blebbing cell lines. Importantly, AQP1 overexpression reduces bleb lifespan due to faster bleb retraction. This novel finding of AQP1-facilitated bleb retraction requires the activity of the Na+/H+ pump as inhibition of the ion transporter, which was found localized to intracellular vesicles, blocked bleb retraction in both cell lines. This study also demonstrated that a differential regulation of cell blebbing by AQP isoforms exists as knockdown of AQP5 had no effect on bleb formation. Data from this study also demonstrates that the lipid signaling PLD2 signals through PA in the LPA-LPAR-Rho-ROCK axis to positively regulate bleb formation in both cell lines. Taken together, this work provides a novel role of AQP1 and Na+/H+ pump in regulation of cell blebbing, and this could be exploited in the development of new therapy to treat cancer.

Interaction between BMI and APOE genotype is associated with changes in the plasma long-chain-PUFA response to a fish-oil supplement in healthy participants

BACKGROUND: Carriers of the apolipoprotein E ɛ4 (APOE4) allele are lower responders to a docosahexaenoic acid (DHA) supplement than are noncarriers. This effect could be exacerbated in overweight individuals because DHA metabolism changes according to body mass index (BMI; in kg/m²). OBJECTIVES: We evaluated the plasma fatty acid (FA) response to a DHA-rich supplement in APOE4 carriers and noncarriers consuming a high-saturated fat diet (HSF diet) and, in addition, evaluated whether being overweight changed this response. DESIGN: This study was part of the SATgenɛ trial. Forty-one APOE4 carriers and 41 noncarriers were prospectively recruited and consumed an HSF diet for 8-wk followed by 8 wk of consumption of an HSF diet with the addition of DHA and eicosapentaenoic acid (EPA) (HSF + DHA diet; 3.45 g DHA/d and 0.5 g EPA/d). Fasting plasma samples were collected at the end of each intervention diet. Plasma total lipids (TLs) were separated into free FAs, neutral lipids (NLs), and phospholipids by using solid-phase extraction, and FA profiles in each lipid class were quantified by using gas chromatography. RESULTS: Because the plasma FA response to the HSF + DHA diet was correlated with BMI in APOE4 carriers but not in noncarriers, the following 2 groups were formed according to the BMI median: low BMI (<25.5) and high BMI (≥25.5). In response to the HSF + DHA diet, there were significant BMI × genotype interactions for changes in plasma concentrations of arachidonic acid and DHA in phospholipids and TLs and of EPA in NLs and TLs (P ≤ 0.05). APOE4 carriers were lower plasma responders to the DHA supplement than were noncarriers but only in the high-BMI group. CONCLUSIONS: Our findings indicate that apolipoprotein E genotype and BMI may be important variables that determine the plasma long-chain PUFA response to dietary fat manipulation. APOE4 carriers with BMI ≥25.5 may need higher intakes of DHA for cardiovascular or other health benefits than do noncarriers

Regurgitated bodies: presenting and representing trauma in 'The Act of Killing'

Focusing on The Act of Killing, this chapter examines how an “ethics of realism” operates on three key cinematic arenas: genre, authorship and spectatorship. As far as genre is concerned, the film’s realist commitment emerges from where it is least expected, namely from Hollywood genres, such as the musical, the film noir and the western, which are used as documentary, that is to say, as a fantasy realm where perpetrators can confess to their crimes without restraints or fear of punishment, but which nonetheless retains the evidentiary weight of the audiovisual medium. Authorship, in turn, translates as Oppenheimer’s unmistakable auteur signature through his role of self-confessed “infiltrator” who disguises as a sympathiser of the criminals in order to gain first-hand access to the full picture of their acts. One of them, the protagonist Anwar Congo, is clearly affected by post-traumatic stress disorder, and his repetitive reliving of his killings is made to flare up in front of the camera so as to bring back the dead to the present time in their material reality, through his own body, including a harrowing scene of the actor’s unpredictable and uncontrollable retching as he re-enacts the killing of his victims through strangulation. Finally, in the realm of spectatorship, the usual process of illusionistic identification on the part of the spectator is turned onto its head by means of disguising these criminals as amateur filmmakers, led to shoot, act within, and then watch their own film within the film so as to force them to experience beyond any illusion the suffering they had caused.

Space, authenticity and utopia in the hip-hop teen dance film

The dance film flourished in the 2000s in the form of the hip-hop teen dance film. Such films as Save the Last Dance (Thomas Carter, 2001), Honey (Billy Woodruff, 2002) and Step Up (Anne Fletcher, 2006) drew on hip-hop’s dominance of the mainstream music industry and combined the teen film’s pre-existing social problem and musical narratives. Yet various tension were created by their interweaving of representations of post-industrial city youth with the utopian sensibilities of the classical Hollywood musical. Their narratives celebrated hip-hop performance, and depicted dance’s ability to bridge cultural boundaries and bring together couples and communities. These films used hip-hop to define space and identity yet often constructed divisions within their soundscapes, limiting hip-hop’s expressive potential. This article explores the cycle’s celebration of, yet struggle with, hip-hop through examining select films’ interactions between soundscape, narrative and form. It will engage with these films’ attempts to marry the representational, narrative and aesthetic meanings of hip-hop culture with the form and ideologies of the musical genre, particularly the tensions and continuities that arise from their engagement with the genre’s utopian qualities identified by Richard Dyer (1985). Yet whilst these films illustrate the tensions and challenges of combining hip-hop culture and the musical genre, they also demonstrate an effective integration of hip-hop soundscape and the dancing body in their depiction of dance, highlighting both form’s aesthetics of layering, rupture and flow (Rose, 1994: 22).

Sea ice production and water mass modification in the eastern Laptev Sea

A simple polynya flux model driven by standard atmospheric forcing is used to investigate the ice formation that took place during an exceptionally strong and consistent western New Siberian (WNS) polynya event in 2004 in the Laptev Sea. Whether formation rates are high enough to erode the stratification of the water column beneath is examined by adding the brine released during the 2004 polynya event to the average winter density stratification of the water body, preconditioned by summers with a cyclonic atmospheric forcing (comparatively weakly stratified water column). Beforehand, the model performance is tested through a simulation of a well‐documented event in April 2008. Neglecting the replenishment of water masses by advection into the polynya area, we find the probability for the occurrence of density‐driven convection down to the bottom to be low. Our findings can be explained by the distinct vertical density gradient that characterizes the area of the WNS polynya and the apparent lack of extreme events in the eastern Laptev Sea. The simple approach is expected to be sufficiently rigorous, since the simulated event is exceptionally strong and consistent, the ice production and salt rejection rates are likely to be overestimated, and the amount of salt rejected is distrusted over a comparatively weakly stratified water column. We conclude that the observed erosion of the halocline and formation of vertically mixed water layers during a WNS polynya event is therefore predominantly related to wind‐ and tidally driven turbulent mixing processes.

Muriel Rukeyser: poetry and the body

The human body occupies a central place in Rukeyser’s poetry. Her characters’ physical experiences inspire their search for an artistic form and a holistic vision that reconciles the corporeal and conceptual aspects of their life. My thesis deals with Rukeyser’s reconciliation of disparate aspects of existence through the image of the human body and the practical experiences she underwent in her personal life and incorporated in her poetry. I discuss her poetry of the 1940s, where a tension is observed between the artist’s personal life and her art, which she attempts to resolve by adopting an artistic form that accommodates her quotidian experiences. I study, mainly through her poetry of the 1950s, Rukeyser’s poetic technique in the light of her organicist poetics and the combination of tendencies to coercion and suggestiveness distinguishing her style. I examine her portrayal of the suffering body in her poetry of the 1960s and 1970s. By means of their physical experiences, the ill, her despised and the imprisoned protagonists undergo a process of development whereby they perceive the different aspects of their identity and attempt to broaden perspectives on their situation by reconciling them. I argue that Rukeyser’s engagement with physical encounters and with the poem as an inclusive, organic body enables her to reconcile disparate elements in her poetry, such as her personal life and her art, her individual existence and the public world, as well as the distinct aspects of her characters’ identity. Her vatic outlook, which integrates distinct aspects of experience, is consistent with Merleau-Ponty’s idea of human perception as characterised by the two interdependent positions of immanence and transcendence. Rukeyser’s poetry depicts her physical engagement with quotidian events of her life as a factor of artistic inspiration. These situations constitute shared human experiences that enable her to imagine the links binding her to other people and the world at large. The poet’s personal experiences inspire her search for an artistic form that accommodates them. Her perception of the concrete aspect of her individual existence gains significance when it is linked to social and political issues. Both the private and public are thus seen as interconnected, and they affect the existence of each other while retaining their distinctness.

Intake of total and subgroups of fat minimally affect the associations between selected single nucleotide polymorphisms in the PPARγ pathway and changes in anthropometry among European adults from cohorts of the DiOGenes study

BACKGROUND: Although the peroxisome proliferator-activated receptor γ (PPARγ) pathway is central in adipogenesis, it remains unknown whether it influences change in body weight (BW) and whether dietary fat has a modifying effect on the association. OBJECTIVES: We examined whether 27 single nucleotide polymorphisms (SNPs) within 4 genes in the PPARγ pathway are associated with the OR of being a BW gainer or with annual changes in anthropometry and whether intake of total fat, monounsaturated fat, polyunsaturated fat, or saturated fat has a modifying effect on these associations. METHODS: A case-noncase study included 11,048 men and women from cohorts in the European Diet, Obesity and Genes study; 5552 were cases, defined as individuals with the greatest BW gain during follow-up, and 6548 were randomly selected, including 5496 noncases. We selected 4 genes [CCAAT/enhancer binding protein β (CEBPB), phosphoenolpyruvate carboxykinase 2, PPARγ gene (PPARG), and sterol regulatory element binding transcription factor 1] according to evidence about biologic plausibility for interactions with dietary fat in weight regulation. Diet was assessed at baseline, and anthropometry was followed for 7 y. RESULTS: The ORs for being a BW gainer for the 27 genetic variants ranged from 0.87 (95% CI: 0.79, 1.03) to 1.12 (95% CI: 0.96, 1.22) per additional minor allele. Uncorrected, CEBPB rs4253449 had a significant interaction with the intake of total fat and subgroups of fat. The OR for being a BW gainer for each additional rs4253449 minor allele per 100 kcal higher total fat intake was 1.07 (95% CI: 1.02, 1.12; P = 0.008), and similar associations were found for subgroups of fat. CONCLUSIONS: Among European men and women, the influence of dietary fat on associations between SNPs in the PPARγ pathway and anthropometry is likely to be absent or marginal. The observed interaction between rs4253449 and dietary fat needs confirmation.