The Role of Regulatory T Cells in Cancer

There has been an explosion of literature focusing on the role of regulatory T (Treg) cells in cancer immunity. It is becoming increasingly clear that Treg cells play an active and significant role in the progression of cancer, and have an important role in suppressing tumor-specific immunity. Thus, there is a clear rationale for developing clinical strategies to diminish their regulatory influences, with the ultimate goal of augmenting antitimor immunity. Therefore, manipulation of Treg cells represent new strategies for cancer treatment. In this Review, I will summarize and review the explosive recent studies demonstrating that Treg cells are increased in patients with malignancies and restoration of antitumor immunity in mice and humans by depletion or reduction of Treg cells. In addition, I will discuss both the prognostic value of Treg cells in tumor progression in tumor-bearing hosts and the rationale for strategies for therapeutic vaccination and immunotherapeutic targeting of Treg cells with drugs and microRNA

Dose Effects of Oxaliplatin on Persistent and Transient Na+ Conductances and the Development of Neurotoxicity

BACKGROUND: Oxaliplatin, a platinum-based chemotherapy utilised in the treatment of colorectal cancer, produces two forms of neurotoxicity--acute sensorimotor neuropathic symptoms and a dose-limiting chronic sensory neuropathy. Given that a Na(+) channelopathy has been proposed as the mechanism underlying acute oxaliplatin-induced neuropathy, the present study aimed to determine specific mechanisms of Na(+) channel dysfunction. METHODOLOGY/PRINCIPAL FINDINGS: Specifically the function of transient and persistent Na(+) currents were followed during treatment and were investigated in relation to oxaliplatin dose level. Eighteen patients were assessed before and after a single oxaliplatin infusion with motor and sensory axonal excitability studies performed on the median nerve at the wrist. While refractoriness (associated with Na(+) channel inactivation) was significantly altered post-oxaliplatin infusion in both motor (Pre: 31.7±6.4%; Post: 68.8±14.5%; P≤.001) and sensory axons (Pre: 31.4±5.4%; Post: 21.4±5.5%; P<.05), strength-duration time constant (marker of persistent Na(+) conductances) was not significantly altered post-infusion (Motor Pre: 0.395±0.01 ms; Post: 0.394±0.02 ms; NS; Sensory Pre:0.544±0.03 ms; Post: 0.535±0.05 ms; NS). However, changes in strength-duration time constant were significantly correlated with changes in refractoriness in motor and sensory axons (Motor correlation coefficient = -.65; P<.05; Sensory correlation coefficient = .67; P<.05). CONCLUSIONS/SIGNIFICANCE: It is concluded that the predominant effect of acute oxaliplatin exposure in human motor and sensory axons is mediated through changes in transient rather than persistent Na(+) conductances. These findings are likely to have implications for the design and trial of neuroprotective strategies

Revealing a novel nociceptive network that links the subthalamic nucleus to pain processing

Pain is a prevalent symptom of Parkinson's disease, and is effectively treated by deep brain stimulation of the subthalamic nucleus (STN). However, the link between pain and the STN remains unclear. In the present work, we report that STN neurons exhibit complex tonic and phasic responses to noxious stimuli using in vivo electrophysiology in rats. We also show that nociception is altered following lesions of the STN, and characterize the role of the superior colliculus and the parabrachial nucleus in the transmission of nociceptive information to the STN, physiologically from both structures and anatomically in the case of the parabrachial nucleus. We show that STN nociceptive responses are abnormal in a rat model of PD, suggesting their dependence on the integrity of the nigrostriatal dopaminergic system. The STN-linked nociceptive network we reveal is likely to be of considerable clinical importance in neurological diseases involving a dysfunction of the basal ganglia

The IceCube Neutrino Observatory, the Pierre Auger Observatory and the Telescope Array: Joint Contribution to the 34th International Cosmic Ray Conference (ICRC 2015)

We have conducted three searches for correlations between ultra-high energy cosmic rays detected by the Telescope Array and the Pierre Auger Observatory, and high-energy neutrino candidate events from IceCube. Two cross-correlation analyses with UHECRs are done: one with 39 cascades from the IceCube `high-energy starting events' sample and the other with 16 high-energy `track events'. The angular separation between the arrival directions of neutrinos and UHECRs is scanned over. The same events are also used in a separate search using a maximum likelihood approach, after the neutrino arrival directions are stacked. To estimate the significance we assume UHECR magnetic deflections to be inversely proportional to their energy, with values $3^\circ$, $6^\circ$ and $9^\circ$ at 100 EeV to allow for the uncertainties on the magnetic field strength and UHECR charge. A similar analysis is performed on stacked UHECR arrival directions and the IceCube sample of through-going muon track events which were optimized for neutrino point-source searches.Comment: one proceeding, the 34th International Cosmic Ray Conference, 30 July - 6 August 2015, The Hague, The Netherlands; will appear in PoS(ICRC2015

Search for Spatial Correlations of Neutrinos with Ultra-high-energy Cosmic Rays

For several decades, the origin of ultra-high-energy cosmic rays (UHECRs) has been an unsolved question of high-energy astrophysics. One approach for solving this puzzle is to correlate UHECRs with high-energy neutrinos, since neutrinos are a direct probe of hadronic interactions of cosmic rays and are not deflected by magnetic fields. In this paper, we present three different approaches for correlating the arrival directions of neutrinos with the arrival directions of UHECRs. The neutrino data are provided by the IceCube Neutrino Observatory and ANTARES, while the UHECR data with energies above ∼50 EeV are provided by the Pierre Auger Observatory and the Telescope Array. All experiments provide increased statistics and improved reconstructions with respect to our previous results reported in 2015. The first analysis uses a high-statistics neutrino sample optimized for point-source searches to search for excesses of neutrino clustering in the vicinity of UHECR directions. The second analysis searches for an excess of UHECRs in the direction of the highest-energy neutrinos. The third analysis searches for an excess of pairs of UHECRs and highest-energy neutrinos on different angular scales. None of the analyses have found a significant excess, and previously reported overfluctuations are reduced in significance. Based on these results, we further constrain the neutrino flux spatially correlated with UHECRs

Update on the Combined Analysis of Muon Measurements from Nine Air Shower Experiments

Over the last two decades, various experiments have measured muon densities in extensive air showers over several orders of magnitude in primary energy. While some experiments observed differences in the muon densities between simulated and experimentally measured air showers, others reported no discrepancies. We will present an update of the meta-analysis of muon measurements from nine air shower experiments, covering shower energies between a few PeV and tens of EeV and muon threshold energies from a few 100 MeV to about 10GeV. In order to compare measurements from different experiments, their energy scale was cross-calibrated and the experimental data has been compared using a universal reference scale based on air shower simulations. Above 10 PeV, we find a muon excess with respect to simulations for all hadronic interaction models, which is increasing with shower energy. For EPOS-LHC and QGSJet-II.04 the significance of the slope of the increase is analyzed in detail under different assumptions of the individual experimental uncertainties