Loss of miR‐101 expression promotes Wnt/β‐catenin signalling pathway activation and malignancy in colon cancer cells

Colorectal cancer (CRC) is the second leading cause of cancer‐related mortality in Western countries. Although the aberrant expression of several microRNAs (oncomiRs) is associated with CRC progression, the molecular mechanisms of this phenomenon are still under investigation. Here we show that miR‐101 expression is differentially impaired in CRC specimens, depending on tumour grade. miR‐101 re‐expression suppresses cell growth in 3D, hypoxic survival and invasive potential in CRC cells showing low levels of miR‐101. Additionally, we provide molecular evidence of a bidirectional regulatory mechanism between miR‐101 expression and important CRC pro‐malignant features, such as inflammation, activation of the Wnt/β‐catenin signalling pathway and epithelial–mesenchymal transition (EMT). We then propose that up‐regulated miR‐101 may function as a tumour suppressor in CRC and that its pharmacological restoration might hamper the aggressive behaviour of CRC in vivo. MiR‐101 expression may also represent a cancer biomarker for CRC diagnosis and prognosis. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

Nanomagnetic Modulation of Tumor Redox State

Modulation of reactive oxygen and nitrogen species in a tumor could be exploited for nanotherapeutic benefits. We investigate the antitumor effect in Walker-256 carcinosarcoma of magnetic nanodots composed of doxorubicin-loaded Fe₃O₄ nanoparticles combined with electromagnetic fields. Treatment using the magnetic nanodot with the largest hysteresis loop area (3402 erg/g) had the greatest antitumor effect with the minimum growth factor 0.49 ± 0.02 day^–1 (compared to 0.58 ± 0.02 day^–1 for conventional doxorubicin). Electron spin resonance spectra of Walker-256 carcinosarcoma treated with the nanodots, indicate an increase of 2.7 times of free iron (that promotes the formation of highly reactive oxygen species), using the nanodot with the largest hysteresis loop area, compared to conventional doxorubicin treatment as well as increases in ubisemiquinone, lactoferrin, NO-FeS-proteins. Hence, we provide evidence that the designed magnetic nanodots can modulate the tumor redox state. We discuss the implications of these results for cancer nanotherapy.     

Cluster Analysis of Extracardiac Control of the Heart Rate in Random-Bred Albino Rats at Rest

Heart rate variability was examined in random-bred albino rats at rest. The rats were clusterized according to activity of autonomic contour of heart rate control. Combination of factor and cluster analyses enhanced informative value of spectrum parameters of the heart rate variability in nonlinear rats grouped by initial neurovegetative status. The contours of central and autonomic regulation describe the most general features of the control influences that realize modulating influences at the heart level via sympathetic and parasympathetic control pathways. Their activity is comprehensively assessed by the normalized power spectrum of variations in the heart rate. Translated from Byulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 147, No. 1, pp. 16–19, January, 2009     

Effect of copper on extracellular levels of key pro-inflammatory molecules in hypothalamic GN11 and primary neurons

Copper dyshomeostasis is responsible for the neurological symptoms observed in the genetically inherited copper-dependent disorders (e.g., Menkes’ and Wilson's diseases), but it has been also shown to have an important role in neurodegenerative diseases such as Alzheimer disease, prion diseases, Parkinson's disease and amyotrophic lateral sclerosis. It is widely accepted that increased extracellular copper levels contribute to neuronal pathogenic process by increasing the production of dangerous radical oxygen species, but the existence of other molecular mechanisms explaining copper neurotoxicity has not been investigated yet. By using a cellular model based on hypothalamic GN11 cultured neurons exposed to copper supplementation and by analysing the cell conditioned media, we try here to identify new molecular events explaining the association between extracellular copper accumulation and neuronal damages. We show here that increased extracellular copper levels produce a wide complex of alterations in the neuronal extracellular environment. In particular, copper affects the secretion of molecules involved in the protection of neurons against oxidative stress, such as cyclophilin A (CypA), or of molecules capable of shifting neuronal cells towards a pro-inflammatory state, such as IL-1α, IL-12, Rantes, neutrophil gelatinase-associated lipocalin (NGAL) and secreted protein acidic and rich in cysteine (SPARC). Copper pro-inflammatory properties have been confirmed by using primary neurons.     

Population pharmacokinetic measures, their estimation and selection of sampling times

In pharmacokinetic (PK) studies, including bioavailability assessment, various population PK measures, such as area under the curve (AUC), maximal concentration (C(max)) and time to maximal concentration (T(max)) are estimated. In this paper we compare a model-based approach, where parameters of a compartmental model are estimated and the explicit formulae for PK measures are used, and a model-independent approach, where numerical integration algorithms are used for AUC and sample estimates for C(max) and T(max). Since regulatory agencies usually require the model-independent estimation of PK measures, we focus on the empirical approach while using the model-based approach and corresponding measures as a benchmark. We show how to "split" a single sampling grid into two or more subsets, which substantially reduces the number of samples taken for each patient, but often has little effect on the precision of estimation of PK measures in terms of mean squared error (MSE). We give explicit formulae for the MSE of the empirical estimator of AUC for a simple example and discuss how costs may be taken into account.     

Apoptosis of hypothalamic neurosecretory cells in stress mice at different stages of ontogenesis

The aim of the present work was to identify the role of cycloferon in the apoptosis of cells in the neurosecretory centers of the hypothalamus in young and old mice in conditions of immobilization stress. Apoptotic cells were identified by staining with ethidium bromide. The optical density of the detection product of the antiapoptotic protein Bcl-2 was also studied in cells of the supraoptic and paraventricular (PVN) nuclei. Cycloferon was found to decrease the level of apoptosis in the neurosecretory centers of the hypothalamus via a Bcl-2-independent pathway. Administration of cycloferon before stress had no effect on the number of apoptotic cells, except in the PVN of old mice, where apoptosis was inhibited. __________ Translated from Morfologiya, Vol. 127, No. 3, pp. 27–29, May–June, 2005.