LIP expression is regulated by IGF-1R signaling and participates in suppression of anoikis

<p>Abstract</p> <p>Background</p> <p>The transcription factor, CCAAT enhancer binding protein-β (C/EBPβ), is expressed as several distinct protein isoforms (LAP1, LAP2 and LIP) that have opposing actions in cellular proliferation and differentiation. Increases in the ratio of LIP/LAP are associated with aggressive, metastatic breast cancer; however, little is known regarding the molecular mechanisms that regulate LIP expression or the biological actions of an increase in the LIP/LAP ratio. Metastasis is highly dependent upon the suppression of anoikis and the role of C/EBPβ and LIP in this anchorage-independent, survival process is currently not known in mammary epithelial cells. IGF-1R signaling is important for the survival of breast cancer cells and crosstalk between IGF-1R and EGFR signaling pathways have been implicated in the development of more aggressive disease. We therefore evaluated in mammary epithelial cells whether IGF-1R signaling regulates the LIP/LAP ratio, analyzed the potential interplay between EGFR and IGF-1R signaling and addressed the biological significance of increased LIP expression in cellular survival and suppression of anoikis.</p> <p>Results</p> <p>Our data provide the first evidence that IGF-1R signaling regulates LIP expression in an EGFR independent manner to increase the LIP/LAP ratio in mammary epithelial cells. Although crosstalk between IGF-1R signaling and EGFR signaling is detectable in MCF10A cells, this crosstalk is not required for the IGF-1 mediated regulation of LIP expression. Rather, the critical regulator of IGF-1 induced LIP expression appears to be EGFR-independent, Akt activity. Our data also demonstrate that increases in LIP expression promote cell survival via suppression of anoikis. Likewise, knockdown of total C/EBPβ leads to increased cell death and suggest that C/EBPβ expression is important for survival and resistance to anoikis. IGF-1 treatment can partially rescue vector control cells from anoikis; however, cells with reduced C/EBPβ expression do not survive anoikis.</p> <p>Conclusions</p> <p>Taken together, our data demonstrate that IGF-1R signaling regulates LIP expression in an EGFR independent manner to increase the LIP/LAP ratio in mammary epithelial cells. C/EBPβ expression and elevations in LIP play an important role in regulating cellular survival via suppression of anoikis, in an IGF-1R mediated context or in a manner independent of IGF-1R signaling.</p

Motives and Correlates of Anabolic-Androgenic Steroid Use With Stimulant Polypharmacy

Individuals who use anabolic-androgenic steroids (AAS) may engage in concurrent psychoactive drug use recreationally and/or as an additional training aid. Aside from cannabis, individuals who use AAS most commonly report concurrent use of stimulants such as amphetamines and cocaine. In this study, we examine demographic characteristics, frequency of heavy drinking, and nightclubbing in a sample of 993 men from the Global Drug Survey 2015 who reported both AAS and psychoactive drug use before exploring the relationship between motivation for AAS use and the propensity to concurrently engage with stimulant-type substances. Results of a logistic regression analysis suggest that the propensity for concurrent use of AAS and stimulants is greater when AAS use is motivated by weight loss goals, while performance goals are associated with reduced odds of concurrent stimulant use. Identifying individuals who are at risk of polydrug use and associated harms can inform targeted harm reduction strategies

The modes of administration of anabolic-androgenic steroid users (AAS): Are non-injecting people who use steroids overlooked?

Introduction: There is increasing public health concern about the use of anabolic-androgenic steroids (AAS). Understanding of drug use patterns and practices is important if we are to develop appropriate risk-reduction interventions. Yet, much remains unclear about the modes of administration adopted by AAS users. Methods: We used data from a sub-sample of participants from the Global Drug Survey 2015; males who reported using injectable or oral AAS in their lifetime (n=1008). Results: Amongst our sample, approximately one third (35.62%) reported using only injectable AAS during their lifetime while 35.84% reported using only oral, with less than one third (28.54%) using both. Conclusion: These findings suggest there may be a sub-population of individuals who only use AAS orally. Needle and syringe programs (NSPs) are currently the primary point of health service engagement; forming the main healthcare environment for medical and harm reduction advice on steroids. Yet, NSP-based resources are unlikely to reach or be appropriate to those who do not inject AAS. While there is a general need for health services to be more accessible when it comes to AAS use, non-injectors are an overlooked group that require attention

Aggregation and fragmentation dynamics of inertial particles in chaotic flows

Inertial particles advected in chaotic flows often accumulate in strange attractors. While moving in these fractal sets they usually approach each other and collide. Here we consider inertial particles aggregating upon collision. The new particles formed in this process are larger and follow the equation of motion with a new parameter. These particles can in turn fragment when they reach a certain size or shear forces become sufficiently large. The resulting system consists of a large set of coexisting dynamical systems with a varying number of particles. We find that the combination of aggregation and fragmentation leads to an asymptotic steady state. The asymptotic particle size distribution depends on the mechanism of fragmentation. The size distributions resulting from this model are consistent with those found in rain drop statistics and in stirring tank experiments.Comment: 4 pages, 4 figure

Fusion rate enhancement due to energy spread of colliding nuclei

Experimental results for sub-barrier nuclear fusion reactions show cross section enhancements with respect to bare nuclei which are generally larger than those expected according to electron screening calculations. We point out that energy spread of target or projectile nuclei is a mechanism which generally provides fusion enhancement. We present a general formula for calculating the enhancement factor and we provide quantitative estimate for effects due to thermal motion, vibrations inside atomic, molecular or crystal system, and due to finite beam energy width. All these effects are marginal at the energies which are presently measurable, however they have to be considered in future experiments at still lower energies. This study allows to exclude several effects as possible explanation of the observed anomalous fusion enhancements, which remain a mistery.Comment: 17 pages with 3 ps figure included. Revtex styl

Short-term changes in nightlife attendance and patron intoxication following alcohol restrictions in Queensland, Australia

Background: This study aims to explore short-term changes following the introduction of alcohol restrictions (most notably 2 am to 3 am last drinks). We examined patterns of nightlife attendance, intoxication, and alcohol use among patrons shortly before and after restrictions were introduced in Fortitude Valley, Brisbane: the largest nighttime entertainment precinct of Queensland. Methods: Street-intercept patron interviews were conducted in Fortitude Valley in June (n = 497) and July (n = 562) 2016. A pre-post design was used to assess changes in time spent out drinking/partying prior to the interview, time of arrival in the precinct, pre-drinking, and blood alcohol concentration (BAC). Results: Regression models indicated that after the policy introduction, the proportion of people arriving at Fortitude Valley before 10:00 pm increased (OR = 1.38; 95% CI = 1.04, 1.82). Participants reported going out, on average, one hour earlier after the intervention (β = − 0.17; 95% CI = 0.11, 0.22). There was a decrease (RRR = 0.58; 95% CI = 0.43, 0.79) in the proportion of participants who had a high level of intoxication (BAC ≥0.10 g/dL) postintervention. No other significant differences were found. Conclusions: Earlier cessation of alcohol sales and stopping the sale of rapid intoxication drinks after midnight was associated with people arriving in Fortitude Valley earlier. Though legislative loopholes allowed some venues to continue trading to 5 am, the proportion of people in the precinct who were highly intoxicated decreased after the restriction. Further measurement will be required to determine whether the reduction has persisted

Low energy measurement of the 7Be(p,gamma)8B cross section

We have measured the cross section of the 7Be(p,gamma)8B reaction for E_cm = 185.8 keV, 134.7 keV and 111.7 keV using a radioactive 7Be target (132 mCi). Single and coincidence spectra of beta^+ and alpha particles from 8B and 8Be^* decay, respectively, were measured using a large acceptance spectrometer. The zero energy S factor inferred from these data is 18.5 +/- 2.4 eV b and a weighted mean value of 18.8 +/- 1.7 eV b (theoretical uncertainty included) is deduced when combining this value with our previous results at higher energies.Comment: Accepted for publication in Phys. Rev. Let

Coagulation and fragmentation dynamics of inertial particles

Inertial particles suspended in many natural and industrial flows undergo coagulation upon collisions and fragmentation if their size becomes too large or if they experience large shear. Here we study this coagulation-fragmentation process in time-periodic incompressible flows. We find that this process approaches an asymptotic, dynamical steady state where the average number of particles of each size is roughly constant. We compare the steady-state size distributions corresponding to two fragmentation mechanisms and for different flows and find that the steady state is mostly independent of the coagulation process. While collision rates determine the transient behavior, fragmentation determines the steady state. For example, for fragmentation due to shear, flows that have very different local particle concentrations can result in similar particle size distributions if the temporal or spatial variation of shear forces is similar.Comment: 8 pages, 7 figure

Alterations of immune response of non-small lung cancer with azacytidine

Innovative therapies are needed for advanced Non-Small Cell Lung Cancer (NSCLC). We have undertaken a genomics based, hypothesis driving, approach to query an emerging potential that epigenetic therapy may sensitize to immune checkpoint therapy targeting PD-L1/PD-1 interaction. NSCLC cell lines were treated with the DNA hypomethylating agent azacytidine (AZA - Vidaza) and genes and pathways altered were mapped by genome-wide expression and DNA methylation analyses. AZA-induced pathways were analyzed in The Cancer Genome Atlas (TCGA) project by mapping the derived gene signatures in hundreds of lung adeno (LUAD) and squamous cell carcinoma (LUSC) samples. AZA up-regulates genes and pathways related to both innate and adaptive immunity and genes related to immune evasion in a several NSCLC lines. DNA hypermethylation and low expression of IRF7, an interferon transcription factor, tracks with this signature particularly in LUSC. In concert with these events, AZA up-regulates PD-L1 transcripts and protein, a key ligand-mediator of immune tolerance. Analysis of TCGA samples demonstrates that a significant proportion of primary NSCLC have low expression of AZA-induced immune genes, including PD-L1. We hypothesize that epigenetic therapy combined with blockade of immune checkpoints - in particular the PD-1/PD-L1 pathway - may augment response of NSCLC by shifting the balance between immune activation and immune inhibition, particularly in a subset of NSCLC with low expression of these pathways. Our studies define a biomarker strategy for response in a recently initiated trial to examine the potential of epigenetic therapy to sensitize patients with NSCLC to PD-1 immune checkpoint blockade