Restricted access : women's business ownership in profile

This report presents a profile of women-owned businesses in the United Kingdom. The data is drawn from a survey undertaken by the University of Strathclyde for the Federation of Small Businesses (FSB), published in May 2002. In total, 18,561 FSB members responded to the survey, of whom 1,750 (9%) stated that their business was wholly female-owned. In comparison, nearly 44% of respondents stated that their business was wholly male-owned and 42% that their business was owned jointly by men and women. Women-owned businesses are an important element of the SME sector and, as this profile shows, the characteristics of their businesses are rather different to the majority

Effects of receptor tyrosine kinase inhibitors on VEGF165a- and VEGF165b-stimulated gene transcription in HEK-293 cells expressing human VEGFR2

BACKGROUND AND PURPOSE: Receptor tyrosine kinase inhibitors (RTKIs) targeted at VEGF receptor 2 (VEGFR2) have proved to be attractive approaches to cancer therapy based on their ability to reduce angiogenesis. Here we have undertaken a quantitative analysis of the interaction of RTKIs and two VEGF splice variants, VEGF165a and VEGF165b, with VEGFR2 by studying nuclear factor of activated T-cells (NFAT) reporter gene activity in live HEK-293 cells. EXPERIMENTAL APPROACH: HEK-293 cells expressing the human VEGFR2 and a firefly luciferase reporter gene regulated by an NFAT response element were used for quantitative analysis of the effect of RTKIs on VEGF165a- and VEGF165b-stimulated luciferase gene expression. KEY RESULTS: VEGF165a produced a concentration-dependent activation of the NFAT-luciferase reporter gene in living cells that was inhibited in a non-competitive fashion by four different RTKIs (cediranib, pazopanib, sorafenib and vandetanib). The potency obtained for each RTKI from this analysis was similar to those obtained in binding studies using purified VEGFR2 kinase domains. VEGF165b was a lower-efficacy agonist of the NFAT-luciferase response when compared with VEGF165a. Analysis of the concentration–response data using the operational model of agonism indicated that both VEGF165 isoforms had similar affinity for VEGFR2. CONCLUSIONS AND IMPLICATIONS: Quantitative pharmacological analysis of the interaction of VEGF165 isoforms and RTKIs with VEGFR2 in intact living cells has provided important insights into the relative affinity and efficacy of VEGF165a and VEGF165b for activation of the calcineurinNFAT signalling pathway by this tyrosine kinase receptor

Correlated cryogenic fluorescence microscopy and electron cryo-tomography shows that exogenous TRIM5α can form hexagonal lattices or autophagy aggregates in vivo

Members of the tripartite motif (TRIM) protein family have been shown to assemble into structures in both the nucleus and cytoplasm. One TRIM protein family member, TRIM5α, has been shown to form cytoplasmic bodies involved in restricting retroviruses such as HIV-1. Here we applied cryogenic correlated light and electron microscopy, combined with electron cryo-tomography, to intact mammalian cells expressing YFP-rhTRIM5α and found the presence of hexagonal nets whose arm lengths were similar to those of the hexagonal nets formed by purified TRIM5α in vitro. We also observed YFP-rhTRIM5α within a diversity of structures with characteristics expected for organelles involved in different stages of macroautophagy, including disorganized protein aggregations (sequestosomes), sequestosomes flanked by flat double-membraned vesicles (sequestosome:phagophore complexes), sequestosomes within double-membraned vesicles (autophagosomes), and sequestosomes within multivesicular autophagic vacuoles (amphisomes or autolysosomes). Vaults were also seen in these structures, consistent with their role in autophagy. Our data 1) support recent reports that TRIM5α can form both well-organized signaling complexes and nonsignaling aggregates, 2) offer images of the macroautophagy pathway in a near-native state, and 3) reveal that vaults arrive early in macroautophagy

FGFR2 amplification in colorectal adenocarcinoma

FGFR2 is recurrently amplified in 5% of gastric cancers and 1%–4% of breast cancers; however, this molecular alteration has never been reported in a primary colorectal cancer specimen. Preclinical studies indicate that several FGFR tyrosine-kinase inhibitors (TKIs), such as AZD4547, have in vitro activity against the FGFR2-amplified colorectal cell line, NCI-H716. The efficacy of these inhibitors is currently under investigation in clinical trials for breast and gastric cancer. Thus, better characterizing colorectal tumors for FGFR2 amplification could identify a subset of patients who may benefit from FGFR TKI therapies. Here, we describe a novel FGFR2 amplification identified by clinical next-generation sequencing in a primary colorectal cancer. Further characterization of the tumor by immunohistochemistry showed neuroendocrine differentiation, similar to the reported properties of the NCI-H716 cell line. These findings demonstrate that the spectrum of potentially clinically actionable mutations detected by targeted clinical sequencing panels is not limited to only single-nucleotide polymorphisms and insertions/deletions but also to copy-number alterations.</jats:p

Serum Tumor Necrosis Factor-Alpha Associates with Myocardial Oxygen Demand and Exercise Tolerance in Postmenopausal Women

The functional implications of serum tumor necrosis factor-alpha (TNF-α), a marker of oxidative stress, on hemodynamic parameters at rest and during physical exertion are unclear. The aims of this investigation were to examine the independent associations of TNF-α on myocardial oxygen demand at rest and during submaximal exercise, while also evaluating the association of TNF-α on exercise tolerance. Forty, postmenopausal women, provided blood samples and completed a modified-Balke protocol to measure maximal oxygen uptake (VO2max). Large artery compliance was measured by pulse contour analyses while rate-pressure product (RPP), an index of myocardial oxygen demand, was measured at rest and during two submaximal workloads (i.e., ≈55% and ≈75% VO2max). RPP was calculated by dividing the product of heart rate and systolic blood pressure (via auscultation) by 100. Exercise tolerance corresponded with the cessation of the graded exercise test. During higher-intensity exertion, ≈75% VO2max, multiple linear regression revealed a positive association (r = 0.43; p = 0.015) between TNF-α and RPP while adjusting for maximal heart rate, VO2max, large artery compliance, and percent body fat. Path analyses revealed a significant indirect effect of large artery compliance on exercise tolerance through TNF-α, β = 0.13, CI [0.03, 0.35], indicating greater levels of TNF-α associated with poorer exercise tolerance. These data suggest TNF-α independently associates with myocardial oxygen demand during physical exertion, thus highlighting the utility of higher-intensity efforts to expose important phenomena not apparent at rest. TNF-α also appears to be indirectly associated with the link between large artery compliance and exercise tolerance

Asymptotic behavior of the Kleinberg model

We study Kleinberg navigation (the search of a target in a d-dimensional lattice, where each site is connected to one other random site at distance r, with probability proportional to r^{-a}) by means of an exact master equation for the process. We show that the asymptotic scaling behavior for the delivery time T to a target at distance L scales as (ln L)^2 when a=d, and otherwise as L^x, with x=(d-a)/(d+1-a) for ad+1. These values of x exceed the rigorous lower-bounds established by Kleinberg. We also address the situation where there is a finite probability for the message to get lost along its way and find short delivery times (conditioned upon arrival) for a wide range of a's