Cancerous stem cells: deviant stem cells with cancer-causing misbehavior

Stem cells maintain homeostasis in adult tissues via self-renewal and generation of terminally differentiated cells. Alterations in this intricate balance can result in disease. It has become increasingly evident that cancer can be initiated at the level of stem cells. Therefore, understanding what causes stem cells to become cancerous may lead to new therapeutic approaches. Multiple signaling pathways ultimately affect stem cell survival and proliferation, thus maintaining homeostasis in the gut. Changes in these pathways could perturb normal stem cell behavior, leading to cancerous stem cells. In addition, cancerous stem cells show resistance to current therapies and may lead to a dangerous selection process resulting in recurrence and metastasis. Genomic instability, the driving force of mutation and resistance, may give cancerous stem cells an adaptive advantage, especially when subjected to cancer therapies. Targeting the unique characteristics of cancerous stem cells to promote either terminal differentiation or destruction would effectively eradicate cancer and improve patient care and survival

Pharmacologically blocking p53-dependent apoptosis protects intestinal stem cells and mice from radiation.

Exposure to high levels of ionizing radiation (IR) leads to debilitating and dose-limiting gastrointestinal (GI) toxicity. Using three-dimensional mouse crypt culture, we demonstrated that p53 target PUMA mediates radiation-induced apoptosis via a cell-intrinsic mechanism, and identified the GSK-3 inhibitor CHIR99021 as a potent radioprotector. CHIR99021 treatment improved Lgr5+ cell survival and crypt regeneration after radiation in culture and mice. CHIR99021 treatment specifically blocked apoptosis and PUMA induction and K120 acetylation of p53 mediated by acetyl-transferase Tip60, while it had no effect on p53 stabilization, phosphorylation or p21 induction. CHIR99021 also protected human intestinal cultures from radiation by PUMA but not p21 suppression. These results demonstrate that p53 posttranslational modifications play a key role in the pathological and apoptotic response of the intestinal stem cells to radiation and can be targeted pharmacologically

Intertester reliability of brachial artery flow-mediated vasodilation using upper and lower arm occlusion in healthy subjects

The assessment of endothelial function as brachial artery flow-mediated vasodilatation is a widely used technique that determines the effect of risk factor intervention and may have the potential to predict the clinical benefit of antiatherogenic therapy. Previous studies suggest that flow-mediated dilation is greater using the upper-arm occlusion technique, but no data are available to compare intertester reliability between technicians. This study was undertaken to compare the amount of hyperemia between upper and lower occlusion techniques and to determine reproducibility between testers. Nineteen healthy adults, ages 25 to 50, were included in the study. Brachial artery vasodilatation was measured 1 and 3 minutes post cuff deflation and was compared with the baseline and expressed as a percent change. There was a tester effect in the percent change in diameter across all measurements. The results of this study reveal inconsistencies between testers when using a blood pressure cuff to induce hyperemia for the assessment of endothelial function through brachial artery flow-mediated vasodilation. However, upper arm as compared to lower arm blood pressure cuff occlusion results in significantly greater hyperemia and vasodilatation, even though there was a difference in measurements between testers

Prenatal exposure to recreational drugs affects global motion perception in preschool children

Chakraborty, A. et al. Prenatal exposure to recreational drugs affects global motion perception in preschool children. Sci. Rep. 5, 16921; doi: 10.1038/srep16921 (2015).Prenatal exposure to recreational drugs impairs motor and cognitive development; however it is currently unknown whether visual brain areas are affected. To address this question, we investigated the effect of prenatal drug exposure on global motion perception, a behavioural measure of processing within the dorsal extrastriate visual cortex that is thought to be particularly vulnerable to abnormal neurodevelopment. Global motion perception was measured in one hundred and forty-five 4.5-year-old children who had been exposed to different combinations of methamphetamine, alcohol, nicotine and marijuana prior to birth and 25 unexposed children. Self-reported drug use by the mothers was verified by meconium analysis. We found that global motion perception was impaired by prenatal exposure to alcohol and improved significantly by exposure to marijuana. Exposure to both drugs prenatally had no effect. Other visual functions such as habitual visual acuity and stereoacuity were not affected by drug exposure. Prenatal exposure to methamphetamine did not influence visual function. Our results demonstrate that prenatal drug exposure can influence a behavioural measure of visual development, but that the effects are dependent on the specific drugs used during pregnancy.This research was supported by the National Institutes on Drug Abuse grants 2RO1DA014948 and RO1DA021757 and the Auckland Medical Research Foundation

Prenatal Predictors of Infant Self-Regulation: The Contributions of Placental DNA Methylation of NR3C1 and Neuroendocrine Activity

We examined whether placental DNA methylation of the glucocorticoid receptor gene, NR3C1 was associated with self-regulation and neuroendocrine responses to a social stressor in infancy. Placenta samples were obtained at birth and mothers and their infants (n = 128) participated in the still-face paradigm when infants were 5 months old. Infant self-regulation following the still-face episode was coded and pre-stress cortisol and cortisol reactivity was assessed in response to the still-face paradigm. A factor analysis of NR3C1 CpG sites revealed two factors: one for CpG sites 1-4 and the other for sites 5-13. DNA methylation of the factor comprising NR3C1 CpG sites 5-13 was related to greater cortisol reactivity and infant self-regulation, but cortisol reactivity was not associated with infant self-regulation. The results reveal that prenatal epigenetic processes may explain part of the development of infant self-regulation

High-speed metamagnetic resistive switching of FeRh through Joule heating

Due to its proximity to room temperature and demonstrated high degree of temperature tunability, the metamagnetic ordering transition in FeRh is attractive for novel high-performance computing devices seeking to use magnetism as the state variable. We demonstrate electrical control of the transition via Joule heating in FeRh wires. Finite element simulations based on abrupt state transition within each domain result in a globally smooth transition that agrees with the experimental findings and provides insight into the thermodynamics involved. We measure a 150 K decrease in transition temperature with currents up to 60 mA, limited only by the dimensions of the device. The sizeable shift in transition temperature scales with current density and wire length, suggesting the absolute resistance and heat dissipation of the substrate are also important. The FeRh phase change is evaluated by pulsed I-V using a variety of bias conditions. We demonstrate high speed (~ ns) memristor-like behavior and report device performance parameters such as switching speed and power consumption that compare favorably with state-of-the-art phase change memristive technologies.Comment: 35 pages, 9 figure

Characterization of acousto-optical interaction in planar silica optical waveguide by the finite element method

A full-vectorial finite element based approach is used to find accurate modal solutions for the acoustic modes in a Ge-doped planar silica optical waveguide. To enhance the accuracy of the solution, the existing structural symmetry is exploited and rigorous analyses of the interactions between the guided acoustic and optical modes are performed. The Stimulated Brillouin Scattering (SBS) frequency and the overlaps between the fundamental and the higher order transverse and longitudinal acoustic modes and the fundamental quasi-TE optical mode are presented