P-rex1 cooperates with PDGFRβ to drive cellular migration in 3D microenvironments

Expression of the Rac-guanine nucleotide exchange factor (RacGEF), P-Rex1 is a key determinant of progression to metastasis in a number of human cancers. In accordance with this proposed role in cancer cell invasion and metastasis, we find that ectopic expression of P-Rex1 in an immortalised human fibroblast cell line is sufficient to drive multiple migratory and invasive phenotypes. The invasive phenotype is greatly enhanced by the presence of a gradient of serum or platelet-derived growth factor, and is dependent upon the expression of functional PDGF receptor β. Consistently, the invasiveness of WM852 melanoma cells, which endogenously express P-Rex1 and PDGFRβ, is opposed by siRNA of either of these proteins. Furthermore, the current model of P-Rex1 activation is advanced through demonstration of P-Rex1 and PDGFRβ as components of the same macromolecular complex. These data suggest that P-Rex1 has an influence on physiological migratory processes, such as invasion of cancer cells, both through effects upon classical Rac1-driven motility and a novel association with RTK signalling complexes

Targeted RNA-Sequencing Enables Detection of Relevant Translocations and Single Nucleotide Variants and Provides a Method for Classification of Hematological Malignancies-RANKING

BACKGROUND: Patients with hematological malignancies (HMs) carry a wide range of chromosomal and molecular abnormalities that impact their prognosis and treatment. Since no current technique can detect all relevant abnormalities, technique(s) are chosen depending on the reason for referral, and abnormalities can be missed. We tested targeted transcriptome sequencing as a single platform to detect all relevant abnormalities and compared it to current techniques. MATERIAL AND METHODS: We performed RNA-sequencing of 1385 genes (TruSight RNA Pan-Cancer, Illumina) in bone marrow from 136 patients with a primary diagnosis of HM. We then applied machine learning to expression profile data to perform leukemia classification, a method we named RANKING. Gene fusions for all the genes in the panel were detected, and overexpression of the genes EVI1, CCND1, and BCL2 was quantified. Single nucleotide variants/indels were analyzed in acute myeloid leukemia (AML), myelodysplastic syndrome and patients with acute lymphoblastic leukemia (ALL) using a virtual myeloid (54 genes) or lymphoid panel (72 genes). RESULTS: RANKING correctly predicted the leukemia classification of all AML and ALL samples and improved classification in 3 patients. Compared to current methods, only one variant was missed, c.2447A>T in KIT (RT-PCR at 10(-4)), and BCL2 overexpression was not seen due to a t(14; 18)(q32; q21) in 2% of the cells. Our RNA-sequencing method also identified 6 additional fusion genes and overexpression of CCND1 due to a t(11; 14)(q13; q32) in 2 samples. CONCLUSIONS: Our combination of targeted RNA-sequencing and data analysis workflow can improve the detection of relevant variants, and expression patterns can assist in establishing HM classification

Kinks in the discrete sine-Gordon model with Kac-Baker long-range interactions

We study effects of Kac-Baker long-range dispersive interaction (LRI) between particles on kink properties in the discrete sine-Gordon model. We show that the kink width increases indefinitely as the range of LRI grows only in the case of strong interparticle coupling. On the contrary, the kink becomes intrinsically localized if the coupling is under some critical value. Correspondingly, the Peierls-Nabarro barrier vanishes as the range of LRI increases for supercritical values of the coupling but remains finite for subcritical values. We demonstrate that LRI essentially transforms the internal dynamics of the kinks, specifically creating their internal localized and quasilocalized modes. We also show that moving kinks radiate plane waves due to break of the Lorentz invariance by LRI.Comment: 11 pages (LaTeX) and 14 figures (Postscript); submitted to Phys. Rev.

Sick leave among home-care personnel: a longitudinal study of risk factors

BACKGROUND: Sick leave due to neck, shoulder and back disorders (NSBD) is higher among health-care workers, especially nursing aides/assistant nurses, compared with employees in other occupations. More information is needed about predictors of sick leave among health care workers. The aim of the study was to assess whether self-reported factors related to health, work and leisure time could predict: 1) future certified sick leave due to any cause, in nursing aides/assistant nurses (Study group I) and 2) future self-reported sick leave due to NSBD in nursing aides/assistant nurses (Study group II). METHODS: Study group I, comprised 443 female nursing aides/assistant nurses, not on sick leave at baseline when a questionnaire was completed. Data on certified sick leave were collected after 18 months. Study group II comprised 274 of the women, who at baseline reported no sick leave during the preceding year due to NSBD and who participated at the 18 month follow-up. Data on sick leave due to NSBD were collected from the questionnaire at 18 months. The associations between future sick leave and factors related to health, work and leisure time were tested by logistic regression analyses. RESULTS: Health-related factors such as previous low back disorders (OR: 1.89; 95% CI 1.20–2.97) and previous sick leave (OR 6.40; 95%CI 3.97–10.31), were associated with a higher risk of future sick leave due to any cause. Factors related to health, work and leisure time, i.e. previous low back disorders (OR: 4.45; 95% CI 1.27–15.77) previous sick leave, not due to NSBD (OR 3.30; 95%CI 1.33–8.17), high strain work (OR 2.34; 95%CI 1.05–5.23) and high perceived physical exertion in domestic work (OR 2.56; 95%CI 1.12–5.86) were associated with a higher risk of future sick leave due to NSBD. In the final analyses, previous low back disorders and previous sick leave remained significant in both study groups. CONCLUSION: The results suggest a focus on previous low back disorders and previous sick leave for the design of early prevention programmes aiming at reducing future sick leave due to any cause, as well as due to NSBD, among nursing aides/assistant nurses. A multifactorial approach may be of importance in the early prevention of sick leave due to NSBD

HST/NICMOS detection of a partially embedded, intermediate-mass pre-main-sequence population in the 30 Doradus Nebula

We present the detection of an intermediate-mass pre-main-sequence population embedded in the nebular filaments surrounding the 30 Doradus region in the Large Magellanic Cloud (LMC) using HST/NICMOS. In addition to four previously known luminous Class I infrared ``protostars,'' the NICMOS data reveal 20 new sources with intrinsic infrared excess similar to Galactic pre-main sequence stars. Based on their infrared brightness, these objects can be identified as the LMC equivalent of Galactic pre-main sequence stars. The faintest LMC Young Stellar Objects in the sample have colors similar to T Tauri and have about the same brightness as T Tauri if placed at the distance of the LMC. We find no evidence for a lower-mass cut-off in the initial mass function. Instead, the whole spectrum of stellar masses from pre-main sequence stars with ~1.5Mo to massive O stars still embedded in dense knots appears to be present in the nebular filaments. The majority of the young stellar objects can be found to the north of the central starburst cluster R136. This region is very likely evolving into an OB association.Comment: 9 pages, 4 figures, uses emulateapj.sty and psfig.sty. accepted for publication in the Astronomical Journal (August 2001 issue

A comparison of complementary measures of vitamin B6 status, function, and metabolism in the European Prospective Investigation into Cancer and Nutrition (EPIC) study

Background: Vitamin B6 insufficiency has been linked to increased risk of cancer and other chronic diseases. The circulating concentration of pyridoxal 5'-phosphate (PLP) is a commonly used measure of vitamin B6 status. Ratios of substrates indicating PLP coenzymatic function and metabolism may be useful complementary measures to further explore the role of vitamin B6 in health. Objectives: We explored the sensitivity of 5 outcomes, namely PLP concentration, homocysteine:cysteine (Hcy:Cys), cystathionine:cysteine (Cysta:Cys), the 3´-hydroxykynurenine ratio (HKr), and the 4-pyridoxic acid ratio (PAr) to vitamin B6 intake as well as personal and lifestyle characteristics. Medthods: Dietary intake and biomarker data were collected from participants from 3 nested case-control studies within the European Prospective Investigation into Cancer and Nutrition (EPIC). Bayesian regression models assessed the associations of the 5 biomarker outcomes with vitamin B6 intake and personal and lifestyle covariates. Analogous models examined the relations of Hcy:Cys, Cysta:Cys, and HKr with PLP. Results: In total, 4608 participants were included in the analyses. Vitamin B6 intake was most strongly associated with PLP, moderately associated with Hcy:Cys, Cysta:Cys, and HKr, and not associated with PAr (fold change in marker given a doubling of vitamin B6 intake: PLP 1.60 [95% credible interval (CrI): 1.50, 1.71]; Hcy:Cys 0.87 [95% CrI: 0.84, 0.90]; Cysta:Cys 0.89 [95% CrI: 0.84, 0.94]; HKr 0.88 [95% CrI: 0.85, 0.91]; PAr 1.00 [95% CrI: 0.95, 1.05]). PAr was most sensitive to age, and HKr was least sensitive to BMI and alcohol intake. Sex and menopause status were strongly associated with all 5 markers. Conclusions: We found that 5 different markers, capturing different aspects of vitamin B6-related biological processes, varied in their associations with vitamin B6 intake and personal and lifestyle predictors

Living on social assistance with chronic illness: Buffering and undermining features to well-being

<p>Abstract</p> <p>Background</p> <p>In Sweden, the social security and sickness insurance systems are comprehensive and aim to provide people whose illness prevents them from earning their own living, with either sickness benefits or disability pension. Some, however, are not entitled to these benefits or receive social insurance benefits at a level too low for subsistence, and are referred to social assistance. The purpose of this study was to explore in depth how social assistance recipients with chronic illness perceive and respond to the experience of living on social assistance.</p> <p>Methods</p> <p>Seventeen in-depth interviews were carried out with chronically ill people who had received social assistance for several years. Grounded theory informed the design of the study.</p> <p>Results</p> <p>The study showed that different strategies (living one day at a time, taking steps forwards and backwards and making attempts to find ways out of the situation) were employed by social assistance recipients to maintain or improve their well-being. Contextual features like the prevailing welfare system, public services and the local neighbourhood could buffer or undermine these strategies and their overall well-being. These features together influenced how interviewees perceived their situation, the possible ways out of the situation and the consequences for their well-being.</p> <p>Conclusion</p> <p>From this study it is evident that the way in which individuals on social assistance interact with services and how they are treated by professionals plays an important role in their well-being, in combination with what kind of help and support is available for recipients through the welfare system. In this respect, persons living on social assistance with chronic illness are particularly vulnerable. This study suggests that more effort should be made to find long term solutions concerning income support, rehabilitation and other services provided to this group.</p

Gender roles and their influence on life prospects for women in urban Karachi, Pakistan: a qualitative study

Pakistan is a patriarchal society where men are the primary authority figures and women are subordinate. This has serious implications on women&#x0027;s and men&#x0027;s life prospects.The aim was to explore current gender roles in urban Pakistan, how these are reproduced and maintained and influence men&#x0027;s and women&#x0027;s life circumstances.Five focus group discussions were conducted, including 28 women representing employed, unemployed, educated and uneducated women from different socio-economic strata. Manifest and latent content analyses were applied. Two major themes emerged during analysis: &#x2018;Reiteration of gender roles&#x2019; and &#x2018;Agents of change&#x2019;. The first theme included perceptions of traditional gender roles and how these preserve women&#x0027;s subordination. The power gradient, with men holding a superior position in relation to women, distinctive features in the culture and the role of the extended family were considered to interact to suppress women. The second theme included agents of change, where the role of education was prominent as well as the role of mass media. It was further emphasised that the younger generation was more positive to modernisation of gender roles than the elder generation.This study reveals serious gender inequalities and human rights violations against women in the Pakistani society. The unequal gender roles were perceived as static and enforced by structures imbedded in society. Women routinely faced serious restrictions and limitations of autonomy. However, attainment of higher levels of education especially not only for women but also for men was viewed as an agent towards change. Furthermore, mass media was perceived as having a positive role to play in supporting women&#x0027;s empowerment