Influence of opioids on immune function in patients with cancer pain: from bench to bedside

In patients with cancer, opioids are principally used for the management of acute surgical and chronic cancer-related pain. However, opioids have many non-analgesic effects, including direct and indirect effects on cancer cells and on anti-tumour immunity (NK cells, macrophages and T-cells). Direct effects on immune cells are manifested via opioid and non-opioid toll-like receptors, whereas indirect effects are manifested via the sympathetic nervous system and hypothalamic–pituitary–adrenal axis. Opioids can also decrease/alter immune cell infiltration into the tumour micro-environment. Animal models have shown that this is not a class effect, in that morphine and fentanyl suppress NK cell cytotoxicity; buprenorphine does not affect NK cell cytotoxicity, whereas tramadol increases NK cell cytotoxicity, reducing metastasis. In healthy individuals, morphine suppresses and fentanyl enhances NK cell cytotoxicity. In patients undergoing surgery, fentanyl decreased and tramadol increased NK cell cytotoxicity; clinical outcomes were not determined. Meta-analyses of opioid-sparing surgical studies report an association between improved recurrence-free and/or overall survival with regional/neuraxial anaesthesia compared with systemic opioids. In patients receiving opioids for non-surgical cancer-related pain, morphine has variable effects on immunity; clinical outcomes were not assessed. Although there is a potential association between systemic opioid administration and shorter survival in cancer patients with a prognosis of months to years, studies have not been designed to primarily assess survival, as a consequence of which causality cannot be apportioned. Pain is immunosuppressive, so analgesia is important. Opioids for cancer-related pain will continue to be recommended until definitive data on the effects of opioids on clinical outcomes in specific patient groups becomes available

From UV to NIR: A Full-Spectrum Metal-Free Photocatalyst for Efficient Polymer Synthesis in Aqueous Conditions

Photo‐mediation offers unparalleled spatiotemporal control over controlled radical polymerizations (CRP). Photo‐induced electron/energy transfer reversible addition–fragmentation chain transfer (PET‐RAFT) polymerization is particularly versatile owing to its oxygen tolerance and wide range of compatible photocatalysts. In recent years, broadband‐ and near‐infrared (NIR)‐mediated polymerizations have been of particular interest owing to their potential for solar‐driven chemistry and biomedical applications. In this work, we present the first example of a novel photocatalyst for both full broadband‐ and NIR‐mediated CRP in aqueous conditions. Well‐defined polymers were synthesized in water under blue, green, red, and NIR light irradiation. Exploiting the oxygen tolerant and aqueous nature of our system, we also report PET‐RAFT polymerization at the microliter scale in a mammalian cell culture medium

Transmit Power Minimization for MIMO Systems of Exponential Average BER with Fixed Outage Probability

This document is the Accepted Manuscript version of the following article: Dian-Wu Yue, and Yichuang Sun, ‘Transmit Power Minimization for MIMO Systems of Exponential Average BER with Fixed Outage Probability’, Wireless Personal Communications, Vol. 90 (4): 1951-1970, first available online on 20 June 2016. Under embargo. Embargo end date: 20 June 2017. The final publication is available at Springer via https://link.springer.com/article/10.1007%2Fs11277-016-3432-4This paper is concerned with a wireless multiple-antenna system operating in multiple-input multiple-output (MIMO) fading channels with channel state information being known at both transmitter and receiver. By spatiotemporal subchannel selection and power control, it aims to minimize the average transmit power (ATP) of the MIMO system while achieving an exponential type of average bit error rate (BER) for each data stream. Under the constraints on each subchannel that individual outage probability and average BER are given, based on a traditional upper bound and a dynamic upper bound of Q function, two closed-form ATP expressions are derived, respectively, which can result in two different power allocation schemes. Numerical results are provided to validate the theoretical analysis, and show that the power allocation scheme with the dynamic upper bound can achieve more power savings than the one with the traditional upper bound.Peer reviewe

Nanomechanical Detection of Itinerant Electron Spin Flip

Spin is an intrinsically quantum property, characterized by angular momentum. A change in the spin state is equivalent to a change in the angular momentum or mechanical torque. This spin-induced torque has been invoked as the intrinsic mechanism in experiments ranging from the measurements of angular momentum of photons g-factor of metals and magnetic resonance to the magnetization reversal in magnetic multi-layers A spin-polarized current introduced into a nonmagnetic nanowire produces a torque associated with the itinerant electron spin flip. Here, we report direct measurement of this mechanical torque and itinerant electron spin polarization in an integrated nanoscale torsion oscillator, which could yield new information on the itinerancy of the d-band electrons. The unprecedented torque sensitivity of 10^{-22} N m/ \sqrt{Hz} may enable applications for spintronics, precision measurements of CP-violating forces, untwisting of DNA and torque generating molecules.Comment: 14 pages, 4 figures. visit http://nano.bu.edu/ for related paper

Agent based modelling helps in understanding the rules by which fibroblasts support keratinocyte colony formation

Background: Autologous keratincoytes are routinely expanded using irradiated mouse fibroblasts and bovine serum for clinical use. With growing concerns about the safety of these xenobiotic materials, it is desirable to culture keratinocytes in media without animal derived products. An improved understanding of epithelial/mesenchymal interactions could assist in this. Methodology/Principal Findings: A keratincyte/fibroblast o-culture model was developed by extending an agent-based keratinocyte colony formation model to include the response of keratinocytes to both fibroblasts and serum. The model was validated by comparison of the in virtuo and in vitro multicellular behaviour of keratinocytes and fibroblasts in single and co-culture in Greens medium. To test the robustness of the model, several properties of the fibroblasts were changed to investigate their influence on the multicellular morphogenesis of keratinocyes and fibroblasts. The model was then used to generate hypotheses to explore the interactions of both proliferative and growth arrested fibroblasts with keratinocytes. The key predictions arising from the model which were confirmed by in vitro experiments were that 1) the ratio of fibroblasts to keratinocytes would critically influence keratinocyte colony expansion, 2) this ratio needed to be optimum at the beginning of the co-culture, 3) proliferative fibroblasts would be more effective than irradiated cells in expanding keratinocytes and 4) in the presence of an adequate number of fibroblasts, keratinocyte expansion would be independent of serum. Conclusions: A closely associated computational and biological approach is a powerful tool for understanding complex biological systems such as the interactions between keratinocytes and fibroblasts. The key outcome of this study is the finding that the early addition of a critical ratio of proliferative fibroblasts can give rapid keratinocyte expansion without the use of irradiated mouse fibroblasts and bovine serum

Stimulation of Na⁺/H⁺ Exchanger Isoform 1 Promotes Microglial Migration

Regulation of microglial migration is not well understood. In this study, we proposed that Na+/H+ exchanger isoform 1 (NHE-1) is important in microglial migration. NHE-1 protein was co-localized with cytoskeletal protein ezrin in lamellipodia of microglia and maintained its more alkaline intracellular pH (pHi). Chemoattractant bradykinin (BK) stimulated microglial migration by increasing lamellipodial area and protrusion rate, but reducing lamellipodial persistence time. Interestingly, blocking NHE-1 activity with its potent inhibitor HOE 642 not only acidified microglia, abolished the BK-triggered dynamic changes of lamellipodia, but also reduced microglial motility and microchemotaxis in response to BK. In addition, NHE-1 activation resulted in intracellular Na+ loading as well as intracellular Ca2+ elevation mediated by stimulating reverse mode operation of Na+/Ca2+ exchange (NCXrev). Taken together, our study shows that NHE-1 protein is abundantly expressed in microglial lamellipodia and maintains alkaline pHi in response to BK stimulation. In addition, NHE-1 and NCXrev play a concerted role in BK-induced microglial migration via Na+ and Ca2+ signaling. © 2013 Shi et al

Intervention effects of Ganoderma lucidum spores on epileptiform discharge hippocampal neurons and expression of Neurotrophin-4 and N-Cadherin

Epilepsy can cause cerebral transient dysfunctions. Ganoderma lucidum spores (GLS), a traditional Chinese medicinal herb, has shown some antiepileptic effects in our previous studies. This was the first study of the effects of GLS on cultured primary hippocampal neurons, treated with Mg2+ free medium. This in vitro model of epileptiform discharge hippocampal neurons allowed us to investigate the anti-epileptic effects and mechanism of GLS activity. Primary hippocampal neurons from <1 day old rats were cultured and their morphologies observed under fluorescence microscope. Neurons were confirmed by immunofluorescent staining of neuron specific enolase (NSE). Sterile method for GLS generation was investigated and serial dilutions of GLS were used to test the maximum non-toxic concentration of GLS on hippocampal neurons. The optimized concentration of GLS of 0.122 mg/ml was identified and used for subsequent analysis. Using the in vitro model, hippocampal neurons were divided into 4 groups for subsequent treatment i) control, ii) model (incubated with Mg2+ free medium for 3 hours), iii) GLS group I (incubated with Mg2+ free medium containing GLS for 3 hours and replaced with normal medium and incubated for 6 hours) and iv) GLS group II (neurons incubated with Mg2+ free medium for 3 hours then replaced with a normal medium containing GLS for 6 hours). Neurotrophin-4 and N-Cadherin protein expression were detected using Western blot. The results showed that the number of normal hippocampal neurons increased and the morphologies of hippocampal neurons were well preserved after GLS treatment. Furthermore, the expression of neurotrophin-4 was significantly increased while the expression of N-Cadherin was decreased in the GLS treated group compared with the model group. This data indicates that GLS may protect hippocampal neurons by promoting neurotrophin-4 expression and inhibiting N-Cadherin expression

Neural Dynamics during Anoxia and the “Wave of Death”

Recent experiments in rats have shown the occurrence of a high amplitude slow brain wave in the EEG approximately 1 minute after decapitation, with a duration of 5–15 s (van Rijn et al, PLoS One 6, e16514, 2011) that was presumed to signify the death of brain neurons. We present a computational model of a single neuron and its intra- and extracellular ion concentrations, which shows the physiological mechanism for this observation. The wave is caused by membrane potential oscillations, that occur after the cessation of activity of the sodium-potassium pumps has lead to an excess of extracellular potassium. These oscillations can be described by the Hodgkin-Huxley equations for the sodium and potassium channels, and result in a sudden change in mean membrane voltage. In combination with a high-pass filter, this sudden depolarization leads to a wave in the EEG. We discuss that this process is not necessarily irreversible

The inflammatory microenvironment in colorectal neoplasia

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