Investigating the role of Hedgehog/GLI1 signaling in glioblastoma cell response to temozolomide.

Resistance to chemotherapy substantially hinders successful glioblastoma (GBM) treatment, contributing to an almost 100% mortality rate. Resistance to the frontline chemotherapy, temozolomide (TMZ), arises from numerous signaling pathways that are deregulated in GBM, including Hedgehog (Hh) signaling. Here, we investigate suppression of Hh signaling as an adjuvant to TMZ using U87-MG and T98G cell lines as in vitro models of GBM. We found that silencing GLI1 with siRNA reduces cell metabolic activity by up to 30% in combination with TMZ and reduces multidrug efflux activity by 2.5-fold. Additionally, pharmacological GLI inhibition modulates nuclear p53 levels and decreases MGMT expression in combination with TMZ. While we surprisingly found that silencing GLI1 does not induce apoptosis in the absence of TMZ co-treatment, we discovered silencing GLI1 without TMZ co-treatment induces senescence as evidenced by a significant 2.3-fold increase in senescence associated β-galactosidase staining, and this occurs in a loss of PTEN-dependent manner. Finally, we show that GLI inhibition increases apoptosis in glioma stem-like cells by up to 6.8-fold in combination with TMZ, and this reduces the size and number of neurospheres grown from glioma stem-like cells. In aggregate, our data warrant the continued investigation of Hh pathway inhibitors as adjuvants to TMZ chemotherapy and highlight the importance of identifying signaling pathways that determine whether co-treatment will be successful

The characteristics of reflexivity of younger and middle adolescents

The article is devoted to the problem of development of reflection in the adolescence at the age 11–12 and 13–14. It is shown that there are differences in development of reflexivity of younger and middle adolescents. The structure of relations between reflexivity and locus of control and empathy is investigated by means of factor analysis. The specific of reflexivity of younger and middle adolescents is analyzed. Data are given is used for adaptation of program aimed for development of younger and middle adolescents’ reflexivity by means of debate technology.В статье рассматривается проблема развития рефлексии у подростков 11–12 и 13–14 лет. Выявлены различия в развитии рефлексивности у младших и средних подростков. Посредством факторного анализа и учена структура связей рефлексивности с локусом контроля и эмпатией, проанализирована специфика рефлексивности младших и средних подростков. Полученные результаты используются для адаптации программы по развитию рефлексивности у данных возрастных групп с помощью технологии «Дебаты»

Arctic air pollution: Challenges and opportunities for the next decade

The Arctic is a sentinel of global change. This region is influenced by multiple physical and socio-economic drivers and feedbacks, impacting both the natural and human environment. Air pollution is one such driver that impacts Arctic climate change, ecosystems and health but significant uncertainties still surround quantification of these effects. Arctic air pollution includes harmful trace gases (e.g. tropospheric ozone) and particles (e.g. black carbon, sulphate) and toxic substances (e.g. polycyclic aromatic hydrocarbons) that can be transported to the Arctic from emission sources located far outside the region, or emitted within the Arctic from activities including shipping, power production, and other industrial activities. This paper qualitatively summarizes the complex science issues motivating the creation of a new international initiative, PACES (air Pollution in the Arctic: Climate, Environment and Societies). Approaches for coordinated, international and interdisciplinary research on this topic are described with the goal to improve predictive capability via new understanding about sources, processes, feedbacks and impacts of Arctic air pollution. Overarching research actions are outlined, in which we describe our recommendations for 1) the development of trans-disciplinary approaches combining social and economic research with investigation of the chemical and physical aspects of Arctic air pollution; 2) increasing the quality and quantity of observations in the Arctic using long-term monitoring and intensive field studies, both at the surface and throughout the troposphere; and 3) developing improved predictive capability across a range of spatial and temporal scales

Leibniz, Acosmism, and Incompossibility

Leibniz claims that God acts in the best possible way, and that this includes creating exactly one world. But worlds are aggregates, and aggregates have a low degree of reality or metaphysical perfection, perhaps none at all. This is Leibniz’s tendency toward acosmism, or the view that there this no such thing as creation-as-a-whole. Many interpreters reconcile Leibniz’s acosmist tendency with the high value of worlds by proposing that God sums the value of each substance created, so that the best world is just the world with the most substances. I call this way of determining the value of a world the Additive Theory of Value (ATV), and argue that it leads to the current and insoluble form of the problem of incompossibility. To avoid the problem, I read “possible worlds” in “God chooses the best of all possible worlds” as referring to God’s ideas of worlds. These ideas, though built up from essences, are themselves unities and so well suited to be the value bearers that Leibniz’s theodicy requires. They have their own value, thanks to their unity, and that unity is not preserved when more essences are added

Placental Pathology in Relation to Uterine Artery Doppler Findings in Pregnancies with Severe Intrauterine Growth Restriction and Abnormal Umbilical Artery Doppler Changes

OBJECTIVES: Current guidelines for diagnosis and management of early-onset intrauterine growth restriction (IUGR) rely on umbilical artery Doppler (UAD), without including uterine artery Doppler (UtAD). We hypothesized that IUGR cases with abnormal UAD but normal UtAD has a different spectrum of placental pathology compared with those with abnormal UtAD. STUDY DESIGN: Retrospective review of pregnancies with sonographic evidence of IUGR and abnormal UAD prior to delivery. Cases with ≥ 1 UtAD record(s) after 18(+0) weeks' gestation and placental pathology were included. Cases were stratified according to initial UtAD pulsatility index (PI) values (n = 196): normal (n = 19; PI < 95th centile for gestational age/no notching), intermediate (n = 69; PI ≥ 95th centile/no/unilateral notching) and abnormal (n = 108; PI ≥ 95th centile/bilateral notching). Pregnancy outcomes and placental pathology were compared between groups. RESULTS: Women in the normal group delivered later than those in the abnormal group (30.1 ± 3.5 vs. 28.0 ± 3.5 weeks; mean ± standard deviation; p = 0.03). Their placentas exhibited higher rates of chronic intervillositis (15.8 vs. 0.9%; p = 0.01), chorangiosis (15.8 vs. 0.9%; p < 0.0001), and massive perivillous fibrin deposition (21.1 vs. 7.4%; p = 0.05), but had lower rates of uteroplacental vascular insufficiency (26.3 vs. 79.6%; p < 0.0001). CONCLUSION: Approximately 10% of pregnancies with early-onset IUGR and abnormal UAD exhibited normal UtAD waveforms. They delivered later, and their placentas exhibited unusual placental pathologies

Detection of pollution transport events southeast of Mexico City using ground-based visible spectroscopy measurements of nitrogen dioxide

This work presents ground based differential optical absorption spectroscopy (DOAS) measurements of nitrogen dioxide (NO&lt;sub&gt;2&lt;/sub&gt;) during the MILAGRO field campaign in March 2006 at the Tenango del Aire research site located to the southeast of Mexico City. The DOAS NO&lt;sub&gt;2&lt;/sub&gt; column density measurements are used in conjunction with ceilometer, meteorological and surface nitric oxide (NO), nitrogen oxides (NO&lt;sub&gt;x&lt;/sub&gt;) and total reactive nitrogen (NO&lt;sub&gt;y&lt;/sub&gt;) measurements to analyze pollution transport events to the southeast of Mexico City during the MILARGO field campaign. The study divides the data set into three case study pollution transport events that occurred at the Tenango del Aire research site. The unique data set is then used to provide an in depth analysis of example days of each of the pollution transport events. An in depth analysis of 13 March 2006, a Case One day, shows the transport of several air pollution plumes during the morning through the Tenango del Aire research site when southerly winds are present and demonstrates how DOAS tropospheric NO&lt;sub&gt;2&lt;/sub&gt; vertical column densities (VCD), surface NO&lt;sub&gt;2&lt;/sub&gt; mixing ratios and ceilometer data are used to determine the vertical homogeneity of the pollution layer. The analysis of 18 March 2006, a Case Two day, shows that when northerly winds are present for the entire day, the air at the Tenango del Aire research site is relatively clean and no major pollution plumes are detected. Case 3 days are characterized by relatively clean air throughout the morning with large DOAS NO&lt;sub&gt;2&lt;/sub&gt; enhancements detected in the afternoon. The analysis of 28 March 2006 show the DOAS NO&lt;sub&gt;2&lt;/sub&gt; enhancements are likely due to lightning activity and demonstrate how suitable ground-based DOAS measruements are for monitoring anthropogenic and natural pollution sources that reside above the mixing layer

A Rare Cause of Renal Mass; A Case Study

A seventy five year old gentleman with the clinical diagnosis of renal tuberculosis was found to have renal squamous cell carcinoma. The clinical presentation and management are being discussed

Spinoza

"Spinoza", second edition. Encyclopedia entry for the Springer Encyclopedia of EM Phil and the Sciences, ed. D. Jalobeanu and C. T. Wolfe