34 research outputs found
PAK4 regulates stemness and progression in endocrine resistant ER-positive metastatic breast cancer
Despite the effectiveness of endocrine therapies to treat estrogen receptor-positive (ER+) breast tumours, two thirds of patients will eventually relapse due to de novo or acquired resistance to these agents. Cancer Stem-like Cells (CSCs), a rare cell population within the tumour, accumulate after anti-estrogen treatments and are likely to contribute to their failure. Here we studied the role of p21-activated kinase 4 (PAK4) as a promising target to overcome endocrine resistance and disease progression in ER+ breast cancers. PAK4 predicts for resistance to tamoxifen and poor prognosis in 2 independent cohorts of ER+ tumours. We observed that PAK4 strongly correlates with CSC activity in metastatic patient-derived samples irrespective of breast cancer subtype. However, PAK4-driven mammosphere-forming CSC activity increases alongside progression only in ER+ metastatic samples. PAK4 activity increases in ER+ models during acquired resistance to endocrine therapies. Targeting PAK4 with either CRT PAKi, a small molecule inhibitor of PAK4, or with specific siRNAs abrogates CSC activity/self-renewal in clinical samples and endocrine-resistant cells. Together, our findings establish that PAK4 regulates stemness during disease progression and that its inhibition reverses endocrine resistance in ER+ breast cancers
Test of the Kolmogorov-Johnson-Mehl-Avrami picture of metastable decay in a model with microscopic dynamics
The Kolmogorov-Johnson-Mehl-Avrami (KJMA) theory for the time evolution of
the order parameter in systems undergoing first-order phase transformations has
been extended by Sekimoto to the level of two-point correlation functions.
Here, this extended KJMA theory is applied to a kinetic Ising lattice-gas
model, in which the elementary kinetic processes act on microscopic length and
time scales. The theoretical framework is used to analyze data from extensive
Monte Carlo simulations. The theory is inherently a mesoscopic continuum
picture, and in principle it requires a large separation between the
microscopic scales and the mesoscopic scales characteristic of the evolving
two-phase structure. Nevertheless, we find excellent quantitative agreement
with the simulations in a large parameter regime, extending remarkably far
towards strong fields (large supersaturations) and correspondingly small
nucleation barriers. The original KJMA theory permits direct measurement of the
order parameter in the metastable phase, and using the extension to correlation
functions one can also perform separate measurements of the nucleation rate and
the average velocity of the convoluted interface between the metastable and
stable phase regions. The values obtained for all three quantities are verified
by other theoretical and computational methods. As these quantities are often
difficult to measure directly during a process of phase transformation, data
analysis using the extended KJMA theory may provide a useful experimental
alternative.Comment: RevTex, 21 pages including 14 ps figures. Submitted to Phys. Rev. B.
One misprint corrected in Eq.(C1
Views on primary prevention of cardiovascular disease - an interview study with Swedish GPs
Background: General practitioners (GPs) have gradually become more involved in the prevention of cardiovascular disease (CVD), both through more frequent prescribing of pharmaceuticals and by giving advice regarding lifestyle factors. Most general practitioners are now faced with decisions about pharmaceutical or non-pharmaceutical treatment for primary prevention every day. The aim of this study was to explore, structure and describe the views on primary prevention of cardiovascular disease in clinical practice among Swedish GPs. Methods: Individual interviews were conducted with 21 GPs in southern Sweden. The interview transcripts were analysed using a qualitative approach, inspired by phenomenography. Results: Two main categories of description emerged during the analysis. One was the degree of reliance on research data regarding the predictability of real risk and the opportunities for primary prevention of CVD. The other was the allocation of responsibility between the patient and the doctor. The GPs showed different views, from being convinced of an actual and predictable risk for the individual to strongly doubting it; from relying firmly on protection from disease by pharmaceutical treatment to strongly questioning its effectiveness in individual cases; and from reliance on prevention of disease by non-pharmaceutical interventions to a total lack of reliance on such measures. Conclusions: The GPs' different views, regarding the rationale for and practical management of primary prevention of CVD, can be interpreted as a reflection of the complexity of patient counselling in primary prevention in clinical practice. The findings have implications for development and implementation of standard treatment guidelines, regarding long-time primary preventive treatment