Chronic pain negatively impacts the quality of life in a variety of patient populations. The current therapeutic repertoire is inadequate in managing patient pain and warrants the development of new ...therapeutics. Adenosine and its four cognate receptors (A1, A2A, A2B and A3) have important roles in physiological and pathophysiological states, including chronic pain. Preclinical and clinical studies have revealed that while adenosine and agonists of the A1 and A2A receptors have antinociceptive properties, their therapeutic utility is limited by adverse cardiovascular side effects. In contrast, our understanding of the A3 receptor is only in its infancy, but exciting preclinical observations of A3 receptor antinociception, which have been bolstered by clinical trials of A3 receptor agonists in other disease states, suggest pain relief without cardiovascular side effects and with sufficient tolerability. Our goal herein is to briefly discuss adenosine and its receptors in the context of pathological pain and to consider the current data regarding A3 receptor‐mediated antinociception. We will highlight recent findings regarding the impact of the A3 receptor on pain pathways and examine the current state of selective A3 receptor agonists used for these studies. The adenosine‐to‐A3 receptor pathway represents an important endogenous system that can be targeted to provide safe, effective pain relief from chronic pain.
In cancer, myeloid cells have tumor-supporting roles. We reported that the protein GPNMB (glycoprotein nonmetastatic B) was profoundly upregulated in macrophages interacting with tumor cells. Here, ...using mouse tumor models, we show that macrophage-derived soluble GPNMB increases tumor growth and metastasis in Gpnmb-mutant mice (DBA/2J). GPNMB triggers in the cancer cells the formation of self-renewing spheroids, which are characterized by the expression of cancer stem cell markers, prolonged cell survival and increased tumor-forming ability. Through the CD44 receptor, GPNMB mechanistically activates tumor cells to express the cytokine IL-33 and its receptor IL-1R1L. We also determined that recombinant IL-33 binding to IL-1R1L is sufficient to induce tumor spheroid formation with features of cancer stem cells. Overall, our results reveal a new paracrine axis, GPNMB and IL-33, which is activated during the cross talk of macrophages with tumor cells and eventually promotes cancer cell survival, the expansion of cancer stem cells and the acquisition of a metastatic phenotype.
General relativity provides us with an extremely powerful tool to extract at the same time astrophysical and cosmological information from the stochastic gravitational-wave backgrounds (SGWBs): the ...cross-correlation with other cosmological tracers, since their anisotropies share a common origin and the same perturbed geodesics. In this Letter we explore the cross-correlation of the cosmological and astrophysical SGWBs with cosmic microwave background (CMB) anisotropies, showing that future GW detectors, such as LISA or BBO, have the ability to measure such cross-correlation signals. We also present, as a new tool in this context, constrained realization maps of the SGWBs extracted from the high-resolution CMB Planck maps. This technique allows, in the low-noise regime, to faithfully reconstruct the expected SGWB map by starting from CMB measurements.
The simplest inflationary models present us with few observable parameters to discriminate between them. A detection of features in the spectra of primordial density perturbations could provide ...valuable insights and lead to stringent tests of models of the early Universe. So far, searches for oscillatory features have not produced statistically significant results. In this work we consider a combined search for features in the power spectrum and bispectrum. We show that possible dependencies between the estimates of feature model amplitudes based on the two- and three-point correlators are largely statistically independent under the assumption of the null hypothesis of a nearly Gaussian featureless cosmic microwave background. Building on this conclusion we propose an optimal amplitude estimator for a combined search and study the look-elsewhere effect in feature model surveys. In particular we construct analytic models for the distribution of amplitude estimates that allow for a reliable assessment of the significance of potential findings. We also propose a well-behaved integrated statistic that is designed to detect evidence for models exhibiting features at multiple frequencies.
The direct evaluation of manifestly optimal, cut-sky cosmic microwave background (CMB) power spectrum and bispectrum estimators is numerically very costly, due to the presence of inverse-covariance ...filtering operations. This justifies the investigation of alternative approaches. In this work, we mostly focus on an inpainting algorithm that was introduced in recent CMB analyses to cure cut-sky suboptimalities of bispectrum estimators. First, we show that inpainting can equally be applied to the problem of unbiased estimation of power spectra. We then compare the performance of a novel inpainted CMB temperature power spectrum estimator to the popular apodized pseudo-Cl (PCL) method and demonstrate, both numerically and with analytic arguments, that inpainted power spectrum estimates significantly outperform PCL estimates. Finally, we study the case of cut-sky bispectrum estimators, comparing the performance of three different approaches: inpainting, apodization and a novel low-l leaning scheme. Providing an analytic argument of why the local shape is typically most affected we mainly focus on local-type non-Gaussianity. Our results show that inpainting allows us to achieve optimality also for bispectrum estimation, but interestingly also demonstrate that appropriate apodization, in conjunction with low-l cleaning, can lead to comparable accuracy.
We present the Planck Sky Model (PSM), a parametric model for generating all-sky, few arcminute resolution maps of sky emission at submillimetre to centimetre wavelengths, in both intensity and ...polarisation. Several options are implemented to model the cosmic microwave background, Galactic diffuse emission (synchrotron, free-free, thermal and spinning dust, CO lines), Galactic H ii regions, extragalactic radio sources, dusty galaxies, and thermal and kinetic Sunyaev-Zeldovich signals from clusters of galaxies. Each component is simulated by means of educated interpolations/extrapolations of data sets available at the time of the launch of the Planck mission, complemented by state-of-the-art models of the emission. Distinctive features of the simulations are spatially varying spectral properties of synchrotron and dust; different spectral parameters for each point source; modelling of the clustering properties of extragalactic sources and of the power spectrum of fluctuations in the cosmic infrared background. The PSM enables the production of random realisations of the sky emission, constrained to match observational data within their uncertainties. It is implemented in a software package that is regularly updated with incoming information from observations. The model is expected to serve as a useful tool for optimising planned microwave and sub-millimetre surveys and testing data processing and analysis pipelines. It is, in particular, used to develop and validate data analysis pipelines within the Planck collaboration. A version of the software that can be used for simulating the observations for a variety of experiments is made available on a dedicated website.
Non-genotoxic carcinogens (NGCs) are known to cause perturbations in DNA methylation, which can be an early event leading to changes in gene expression and the onset of carcinogenicity. Phenobarbital ...(PB) has been shown to alter liver DNA methylation and hydroxymethylation patterns in mice in a time dependent manner. The goals of this study were to assess if clofibrate (CFB), a well-studied rodent NGC, would produce epigenetic changes in mice similar to PB, and if a methyl donor supplementation (MDS) would modulate epigenetic and gene expression changes induced by phenobarbital. CByB6F1 mice were treated with 0.5% clofibrate or 0.14% phenobarbital for 7 and 28 days. A subgroup of PB treated and control mice were also fed MDS diet. Liquid Chromatography-Ionization Mass Spectrometry (LC-MS) was used to quantify global liver 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) levels. Gene expression analysis was conducted using Affymetrix microarrays. A decrease in liver 5hmC but not 5mC levels was observed upon treatment with both CFB and PB with varying time of onset. We observed moderate increases in 5hmC levels in PB-treated mice when exposed to MDS diet and lower expression levels of several phenobarbital induced genes involved in cell proliferation, growth, and invasion, suggesting an early modulating effect of methyl donor supplementation. Overall, epigenetic profiling can aid in identifying early mechanism-based biomarkers of non-genotoxic carcinogenicity and increases the quality of cancer risk assessment for candidate drugs. Global DNA methylation assessment by LC-MS is an informative first step toward understanding the risk of carcinogenicity.
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•Phenobarbital and clofibrate cause early (7–28 day) decrease in global DNA hydroxymethylation.•Methyl rich diet transiently reverses phenobarbital induced loss of hydroxymethylation.•Methyl rich diet reduces expression levels of some phenobarbital induced genes.•Decrease of global hydroxymethylation detected by LC/MS may serve as early biomarker of carcinogenicity.
The advantages of immediate implant placement for patients include a reduced number of surgical procedures and a shorter overall treatment time. Disadvantages include a higher risk of aesthetic ...complications. The aim of this study was to compare xenogeneic collagen matrix (XCM) versus a subepithelial connective tissue graft (SCTG) used for soft tissue augmentation in combination with immediate implant placement without provisionalization. Forty-eight patients requiring a single implant-supported rehabilitation were selected and assigned to one of two surgical procedures: immediate implant with SCTG (SCTG group) or immediate implant with XCM (XCM group). Marginal changes in the peri-implant soft tissue and the facial soft tissue thickness (FSTT) were assessed after 12 months. Secondary outcomes included peri-implant health status, aesthetics, patient satisfaction, and perceived pain. All of the implants placed were successfully osseointegrated, resulting in 1-year survival and success rates of 100%. The patients in the SCTG group had a significantly lower mid-buccal marginal level (MBML) recession (P = 0.021) and a greater increase in FSTT (P < 0.001) than the patients in the XCM group. Using xenogeneic collagen matrix during immediate implant placement significantly increased FSTT from the baseline, leading to good aesthetic and patient satisfaction results. However, the connective tissue graft yielded better MBML and FSTT results.
Dental implant placement is a predictable therapy for replacing teeth. Nevertheless, mechanical, biological, and aesthetic complications frequently occur. The aim of this study was to compare the ...clinical outcomes of a xenogeneic collagen matrix (XCM) used at the time of implant placement as an alternative to a subepithelial connective tissue graft (SCTG), for soft tissue augmentation. This was a prospective clinical trial with 12 months of follow-up. In the control group, soft tissue augmentation at the time of implant placement was performed with a SCTG, while in the test group, a XCM was employed. At 12 months postoperative, all xenografts showed no postoperative complications. In both groups, a significantly greater thickness was observed on the buccal and occlusal sides from preoperative to 3 months postoperative (P<0.05). No statistically significant difference in pink aesthetic score (P=0.379, 6 months postoperative) or marginal bone loss (P=0.449 at 3 months postoperative, P=0.778 at 6 months postoperative) was observed between the groups. Statistically significant differences in pain perceived by the patients (P<0.0001) and the time to complete the surgical procedure (P=0.0008) were detected. At 12 months after surgery, XCM provided similar clinical results in terms of soft tissue augmentation on the buccal and occlusal sides as compared with the SCTG.
More than 1.5 billion people worldwide suffer from chronic pain, yet current treatment strategies often lack efficacy or have deleterious side effects in patients. Adenosine is an inhibitory ...neuromodulator that was previously thought to mediate antinociception through the A1 and A2A receptor subtypes. We have since demonstrated that A3AR agonists have potent analgesic actions in preclinical rodent models of neuropathic pain and that A3AR analgesia is independent of adenosine A1 or A2A unwanted effects. Herein, we explored the contribution of the GABA inhibitory system to A3AR-mediated analgesia using well-characterized mouse and rat models of chronic constriction injury (CCI)-induced neuropathic pain. The deregulation of GABA signaling in pathophysiological pain states is well established: GABA signaling can be hampered by a reduction in extracellular GABA synthesis by GAD65 and enhanced extracellular GABA reuptake via the GABA transporter, GAT-1. In neuropathic pain, GABAAR-mediated signaling can be further disrupted by the loss of the KCC2 chloride anion gradient. Here, we demonstrate that A3AR agonists (IB-MECA and MRS5698) reverse neuropathic pain via a spinal mechanism of action that modulates GABA activity. Spinal administration of the GABAA antagonist, bicuculline, disrupted A3AR-mediated analgesia. Furthermore, A3AR-mediated analgesia was associated with reductions in CCI-related GAD65 and GAT-1 serine dephosphorylation as well as an enhancement of KCC2 serine phosphorylation and activity. Our results suggest that A3AR-mediated reversal of neuropathic pain increases modulation of GABA inhibitory neurotransmission both directly and indirectly through protection of KCC2 function, underscoring the unique utility of A3AR agonists in chronic pain.
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