Platelet-activating Factor-receptor agonists generated by chemotherapy thwart host anti-tumor immunity

poster abstractPrevious studies have established that pro-oxidative stressors suppress host immunity due to their ability to generate oxidized glycerophosphocholine (Ox-GPC) lipids with Platelet-activating Factor-receptor (PAF-R) agonist activity. Because many chemotherapeutic agents also induce reactive oxygen species, the present studies were designed to define if chemotherapeutic agents could thwart host anti-tumor immunity against melanoma via PAF-R activation. We demonstrate that treatment of melanoma cell lines in vitro and tumors in vivo with chemotherapeutic agents generates PAF-R-agonists in a process blocked by antioxidants, indicating the involvement of non-enzymatic PAF-R-agonists in this event. In a model system consisting of implantation of two tumors, we show that intratumoral chemotherapy with melphalan or etoposide of one tumor significantly augments the growth of the other (untreated) tumor in wild-type but not PAF-R-deficient hosts. Chemotherapeutic agents-mediated PAF-R-dependent increased tumor growth is blocked by systemic administration of antioxidants and cyclooxygenase-2 inhibitors. In addition, depleting antibodies against regulatory T cells (Tregs) significantly attenuated chemotherapy-mediated growth of untreated tumors, suggesting the role of Tregs in this process. Moreover, using FoxP3EGFP transgenic mice, we show that COX-2 inhibitor blocked intratumoral Tregs, indicating that Tregs are downstream to COX-2. Furthermore, PAF-R agonists were identified in perfusates of patients undergoing isolated limb chemoperfusion for melanoma with melphalan chemotherapy. Finally, various novel Ox-GPCs are identified after chemotherapy by mass spectrometry. These findings provide evidence for a novel and previously unappreciated pathway by which Ox-GPC PAF-R agonists produced as a by-product of chemotherapy modulate tumor growth via the inhibition of anti-tumor immunity. These studies might explain some instances of chemotherapy treatment failure and offer insights into potential therapeutic strategies that could enhance the overall anti-tumor effectiveness of chemotherapy

XMMSL2 J144605.0+685735: a slow tidal disruption event

Aims. We investigate the evolution of X-ray selected tidal disruption events. Methods. New events are found in near real-time data from XMM-Newton slews, and are monitored by multi-wavelength facilities. Results. In August 2016, X-ray emission was detected from the galaxy XMMSL2 J144605.0+685735 (also known as 2MASX 14460522+6857311), that was 20 times higher than an upper limit from 25 years earlier. The X-ray flux was flat for ∼100 days and then fell by a factor of 100 over the following 500 days. The UV flux was stable for the first 400 days before fading by a magnitude, while the optical (U,B,V) bands were roughly constant for 850 days. Optically, the galaxy appears to be quiescent, at a distance of 127 ± 4 Mpc (z = 0.029 ± 0.001) with a spectrum consisting of a young stellar population of 1–5 Gyr in age, an older population, and a total stellar mass of ∼6 × 109 M⊙. The bolometric luminosity peaked at Lbol ∼ 1043 ergs s−1 with an X-ray spectrum that may be modelled by a power law of Γ ∼ 2.6 or Comptonisation of a low-temperature thermal component by thermal electrons. We consider a tidal disruption event to be the most likely cause of the flare. Radio emission was absent in this event down to < 10 μJy, which limits the total energy of a hypothetical off-axis jet to E <  5 × 1050 ergs. The independent behaviour of the optical, UV, and X-ray light curves challenges models where the UV emission is produced by reprocessing of thermal nuclear emission or by stream-stream collisions. We suggest that the observed UV emission may have been produced from a truncated accretion disc and the X-rays from Compton upscattering of these disc photons

Multifunctional Eu-doped NaGd(MoO4)(2) nanoparticles functionalized with poly(L-lysine) for optical and MRI imaging

A method for the synthesis of non-aggregated and highly uniform Eu3+ doped NaGd(MoO4)(2) nanoparticles is reported for the first time. The obtained particles present tetragonal structure, ellipsoidal shape and their size can be varied by adjusting the experimental synthesis parameters. These nanoparticles, which were coated with citrate anions and functionalised with PLL, have also been developed in order to improve their colloidal stability in physiological medium (2-(N-morpholino) ethanesulfonic acid, MES). A study of the luminescent dynamics of the samples as a function of the Eu doping level has been conducted in order to find the optimum nanophosphors, whose magnetic relaxivity and cell viability have also been evaluated for the first time for this system, in order to assess their suitability as multifunctional probes for optical (in vitro) and magnetic bioimaging applications

Lifestyle and comorbid conditions as risk factors for community-acquired pneumonia in outpatient adults (NEUMO-ES-RISK project)

Introduction: Information about community-acquired pneumonia (CAP) risk in primary care is limited. We assess different lifestyle and comorbid conditions as risk factors (RF) for CAP in adults in primary care. Methods: A retrospective-observational-controlled study was designed. Adult CAP cases diagnosed at primary care in Spain between 2009 and 2013 were retrieved using the National Surveillance System of Primary Care Data (BiFAP). Age-matched and sex-matched controls were selected by incidence density sampling (ratio 2:1). Associations are presented as percentages and OR. Binomial regression models were constructed to avoid bias effects. Results: 51 139 patients and 102 372 controls were compared. Mean age (SD) was 61.4 (19.9) years. RF more significantly linked to CAP were: HIV (OR [95% CI]: 5.21 [4.35 to 6.27]), chronic obstructive pulmonary disease (COPD) (2.97 [2.84 to 3.12]), asthma (2.16 [2.07,2.26]), smoking (1.96 [1.91 to 2.02]) and poor dental hygiene (1.45 [1.41 to 1.49]). Average prevalence of any RF was 82.2% in cases and 69.2% in controls (2.05 [2.00 to 2.10]). CAP rate increased with the accumulation of RF and age: risk associated with 1RF was 1.42 (1.37 to 1.47) in 18-60-year-old individuals vs 1.57 (1.49 to 1.66) in >60 years of age, with 2RF 1.88 (1.80 to 1.97) vs 2.35 (2.23, 2.48) and with >/= 3 RF 3.11 (2.95, 3.30) vs 4.34 (4.13 to 4.57). Discussion: Prevalence of RF in adult CAP in primary care is high. Main RFs associated are HIV, COPD, asthma, smoking and poor dental hygiene. Our risk stacking results could help clinicians identify patients at higher risk of pneumonia

Chemotherapeutic agents subvert tumor immunity by generating agonists of platelet-activating factor

Oxidative stress suppresses host immunity by generating oxidized lipid agonists of the platelet-activating factor receptor (PAF-R). Because many classical chemotherapeutic drugs induce reactive oxygen species (ROS), we investigated whether these drugs might subvert host immunity by activating PAF-R. Here, we show that PAF-R agonists are produced in melanoma cells by chemotherapy that is administered in vitro, in vivo, or in human subjects. Structural characterization of the PAF-R agonists induced revealed multiple oxidized glycerophosphocholines that are generated nonenzymatically. In a murine model of melanoma, chemotherapeutic administration could augment tumor growth by a PAF-R-dependent process that could be blocked by treatment with antioxidants or COX-2 inhibitors or by depletion of regulatory T cells. Our findings reveal how PAF-R agonists induced by chemotherapy treatment can promote treatment failure. Furthermore, they offer new insights into how to improve the efficacy of chemotherapy by blocking its heretofore unknown impact on PAF-R activation

Sphingosine 1-phosphate modulates antigen capture by murine langerhans cells via the S1P2 receptor subtype

Dendritic cells (DCs) play a pivotal role in the development of cutaneous contact hypersensitivity (CHS) and atopic dermatitis as they capture and process antigen and present it to T lymphocytes in the lymphoid organs. Recently, it has been indicated that a topical application of the sphingolipid sphingosine 1-phosphate (S1P) prevents the inflammatory response in CHS, but the molecular mechanism is not fully elucidated. Here we indicate that treatment of mice with S1P is connected with an impaired antigen uptake by Langerhans cells (LCs), the initial step of CHS. Most of the known actions of S1P are mediated by a family of five specific G protein-coupled receptors. Our results indicate that S1P inhibits macropinocytosis of the murine LC line XS52 via S1P2 receptor stimulation followed by a reduced phosphatidylinositol 3-kinase (PI3K) activity. As down-regulation of S1P2 not only diminished S1P-mediated action but also enhanced the basal activity of LCs on antigen capture, an autocrine action of S1P has been assumed. Actually, S1P is continuously produced by LCs and secreted via the ATP binding cassette transporter ABCC1 to the extracellular environment. Consequently, inhibition of ABCC1, which decreased extracellular S1P levels, markedly increased the antigen uptake by LCs. Moreover, stimulation of sphingosine kinase activity, the crucial enzyme for S1P formation, is connected not only with enhanced S1P levels but also with diminished antigen capture. These results indicate that S1P is essential in LC homeostasis and influences skin immunity. This is of importance as previous reports suggested an alteration of S1P levels in atopic skin lesions

Oncogenic driver mutations predict outcome in a cohort of head and neck squamous cell carcinoma (HNSCC) patients within a clinical trial

234 diagnostic formalin-fixed paraffin-embedded (FFPE) blocks from homogeneously treated patients with locally advanced head and neck squamous cell carcinoma (HNSCC) within a multicentre phase III clinical trial were characterised. The mutational spectrum was examined by next generation sequencing in the 26 most frequent oncogenic drivers in cancer and correlated with treatment response and survival. Human papillomavirus (HPV) status was measured by p16INK4a immunohistochemistry in oropharyngeal tumours. Clinicopathological features and response to treatment were measured and compared with the sequencing results. The results indicated TP53 as the most mutated gene in locally advanced HNSCC. HPV-positive oropharyngeal tumours were less mutated than HPV-negative tumours in TP53 (p < 0.01). Mutational and HPV status influences patient survival, being mutated or HPV-negative tumours associated with poor overall survival (p < 0.05). No association was found between mutations and clinicopathological features. This study confirmed and expanded previously published genomic characterization data in HNSCC. Survival analysis showed that non-mutated HNSCC tumours associated with better prognosis and lack of mutations can be identified as an important biomarker in HNSCC. Frequent alterations in PI3K pathway in HPV-positive HNSCC could define a promising pathway for pharmacological intervention in this group of tumours

Plasma Membrane Subdomain Compartmentalization Contributes to Distinct Mechanisms of Ceramide Action on Insulin Signaling

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