Immune cell profile of sentinel lymph nodes in patients with malignant melanoma - FOXP3+ cell density in cases with positive sentinel node status is associated with unfavorable clinical outcome

BACKGROUND: Besides being a preferential site of early metastasis, the sentinel lymph node (SLN) is also a privileged site of T-cell priming, and may thus be an appropriate target for investigating cell types involved in antitumor immune reactions. METHODS: In this retrospective study we determined the prevalence of OX40+ activated T lymphocytes, FOXP3+ (forkhead box P3) regulatory T cells, DC-LAMP+ (dendritic cell-lysosomal associated membrane protein) mature dendritic cells (DCs) and CD123+ plasmacytoid DCs by immunohistochemistry in 100 SLNs from 60 melanoma patients. Density values of each cell type in SLNs were compared to those in non-sentinel nodes obtained from block dissections (n = 37), and analyzed with regard to associations with clinicopathological parameters and disease outcome. RESULTS: Sentinel nodes showed elevated amount of all cell types studied in comparison to non-sentinel nodes. Metastatic SLNs had higher density of OX40+ lymphocytes compared to tumor-negative nodes, while no significant difference was observed in the case of the other cell types studied. In patients with positive sentinel node status, high amount of FOXP3+ cells in SLNs was associated with shorter progression-free (P = 0.0011) and overall survival (P = 0.0014), while no significant correlation was found in the case of sentinel-negative patients. The density of OX40+, CD123+ or DC-LAMP+ cells did not show significant association with the outcome of the disease. CONCLUSIONS: Taken together, our results are compatible with the hypothesis of functional competence of sentinel lymph nodes based on the prevalence of the studied immune cells. The density of FOXP3+ lymphocytes showed association with progression and survival in patients with positive SLN status, while the other immune markers studied did not prove of prognostic importance. These results, together with our previous findings on the prognostic value of activated T cells and mature DCs infiltrating primary melanomas, suggest that immune activation-associated markers in the primary tumor may have a higher impact than those in SLNs on the prognosis of the patients. On the other hand, FOXP3+ cell density in SLNs, but not in the primary tumor, was found predictive of disease outcome in melanoma patients

On the defect pattern evolution in sapphire irradiated by swift ions in a broad fluence range

Sapphire samples, irradiated with swift Kr (245 MeV) ions at room temperature in a broad fluence range, were investigated using a continuous and a pulsed positron beam to study the defect structure created by the passage of the ions in depths of a few micrometers. At small doses, monovacancies were identified as dominant defects and positron trapping centres. These monovacancies are assumed to be highly concentrated inside a cylindrical volume around the ion path with an estimated radius of ~1.5 nm. For higher doses a second type of trapping centre emerges. This second class of structural imperfection was associated with the overlap of the individual ion tracks leading to the formation of larger vacancy clusters or voids.http://www.sciencedirect.com/science/article/B6THY-4SHF49N-1S/1/3eb43650299e0466e76cbbbfdaca9fa

Electron transport pathways in isolated chromoplasts from Narcissus pseudonarcissus L.

During daffodil flower development, chloroplasts differentiate into photosynthetically inactive chromoplasts having lost functional photosynthetic reaction centers. Chromoplasts exhibit a respiratory activity reducing oxygen to water and generating ATP. Immunoblots revealed the presence of the plastid terminal oxidase (PTOX), the NAD(P)H dehydrogenase (NDH) complex, the cytochrome b(6)f complex, ATP synthase and several isoforms of ferredoxin-NADP(+) oxidoreductase (FNR), and ferredoxin (Fd). Fluorescence spectroscopy allowed the detection of chlorophyll a in the cytochrome b(6)f complex. Here we characterize the electron transport pathway of chromorespiration by using specific inhibitors for the NDH complex, the cytochrome b(6)f complex, FNR and redox-inactive Fd in which the iron was replaced by gallium. Our data suggest an electron flow via two separate pathways, both reducing plastoquinone (PQ) and using PTOX as oxidase. The first oxidizes NADPH via FNR, Fd and cytochrome b(h) of the cytochrome b(6)f complex, and does not result in the pumping of protons across the membrane. In the second, electron transport takes place via the NDH complex using both NADH and NADPH as electron donor. FNR and Fd are not involved in this pathway. The NDH complex is responsible for the generation of the proton gradient. We propose a model for chromorespiration that may also be relevant for the understanding of chlororespiration and for the characterization of the electron input from Fd to the cytochrome b(6)f complex during cyclic electron transport in chloroplasts.Significance Statement Chromorespiration takes place via two pathways, one depends on FNR, ferredoxin, the cytochrome b6f complex, and the other depends on the NDH complex and is ferredoxin independent. We propose an electron transport via the cytochrome b6f complex that involves neither a Q-cycle nor a high potential electron transport chai

Health-related quality of life impact of cobimetinib in combination with vemurafenib in patients with advanced or metastatic BRAFV600 mutation-positive melanoma

Background: In the coBRIM study, cobimetinib plus vemurafenib (C+V) significantly improved survival outcomes vs placebo and vemurafenib (P+V) in patients with advanced/metastatic BRAF(V600)-mutated melanoma. An analysis of health-related quality of life (HRQOL) from coBRIM is reported.Methods: Patients completing the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) at baseline and >= 1 time point thereafter constituted the analysis population. Change from baseline >= 10 points was considered clinically meaningful.Results: Mean baseline scores for all QLQ-C30 domains were similar between arms. Most on-treatment scores for QLQ-C30 domains were also comparable between arms. A transient deterioration in role function in cycle 1 day 15 (C1D15; -14.7 points) in the P+V arm and improvement in insomnia in the C+V arm at C2D15 (-12.4 points) was observed. Among patients who experienced a >= 10-point change from baseline (responders), between-group differences were greatest for insomnia (16%), social functioning (10%), fatigue (9%) and pain (7%), all favouring C+V. Diarrhoea, photosensitivity reaction, pyrexia, and rash did not meaningfully affect global health status (GHS). Serous retinopathy was associated with a transient decrease in GHS at C1D15 assessment.Conclusions: In patients with advanced/metastatic BRAFV600-mutated melanoma, treatment with C+V maintained HRQOL compared with P+V, with superior efficacy

Development of a PbWO4 Detector for Single-Shot Positron Annihilation Lifetime Spectroscopy at the GBAR Experiment

We have developed a PbWO4 (PWO) detector with a large dynamic range to measure the intensity of a positron beam and the absolute density of the ortho-positronium (o-Ps) cloud it creates. A simulation study shows that a setup based on such detectors may be used to determine the angular distribution of the emission and reflection of o-Ps to reduce part of the uncertainties of the measurement. These will allow to improve the precision in the measurement of the cross-section for the (anti)hydrogen formation by (anti)proton-positronium charge exchange and to optimize the yield of antihydrogen ion which is an essential parameter in the GBAR experiment

Photoperiod affects the phenotype of mitochondrial complex I mutants

Plant mutants for genes encoding subunits of mitochondrial Complex I (CI, NADH:ubiquinone oxidoreductase), the first enzyme of the respiratory chain, display various phenotypes depending on growth conditions. Here, we examined the impact of photoperiod, a major environmental factor controlling plant development, on two Arabidopsis thaliana CI mutants: a new insertion mutant interrupted in both ndufs8.1 and ndufs8.2 genes encoding the NDUFS8 subunit, and the previously characterized ndufs4 CI mutant. In long day (LD) condition, both ndufs8.1 and ndufs8.2 single mutants were indistinguishable from Col-0 at phenotypic and biochemical levels, whereas the ndufs8.1 ndufs8.2 double mutant was devoid of detectable holo-CI assembly/activity, showed higher AOX content/activity and displayed a growth-retardation phenotype similar to that of the ndufs4 mutant. Although growth was more affected in ndufs4 than ndufs8.1 ndufs8.2 under short day (SD) condition, both mutants displayed a similar impairment of growth acceleration after transfer to LD as compared to the WT. Untargeted and targeted metabolomics showed that overall metabolism was less responsive to the SD-to-LD transition in mutants than in the WT. The typical LD acclimation of carbon, nitrogen-assimilation and redox-related parameters was not observed in ndufs8.1 ndufs8. Similarly, NAD(H) content, that was higher in SD condition in both mutants than in Col-0, did not adjust under LD. We propose that altered redox homeostasis and NAD(H) content/redox state control the phenotype of Complex I mutants and photoperiod acclimation in Arabidopsis

Physics with antihydrogen

Performing measurements of the properties of antihydrogen, the bound state of an antiproton and a positron, and comparing the results with those for ordinary hydrogen, has long been seen as a route to test some of the fundamental principles of physics. There has been much experimental progress in this direction in recent years, and antihydrogen is now routinely created and trapped and a range of exciting measurements probing the foundations of modern physics are planned or underway. In this contribution we review the techniques developed to facilitate the capture and manipulation of positrons and antiprotons, along with procedures to bring them together to create antihydrogen. Once formed, the antihydrogen has been detected by its destruction via annihilation or field ionization, and aspects of the methodologies involved are summarized. Magnetic minimum neutral atom traps have been employed to allow some of the antihydrogen created to be held for considerable periods. We describe such devices, and their implementation, along with the cusp magnetic trap used to produce the first evidence for a low-energy beam of antihydrogen. The experiments performed to date on antihydrogen are discussed, including the first observation of a resonant quantum transition and the analyses that have yielded a limit on the electrical neutrality of the anti-atom and placed crude bounds on its gravitational behaviour. Our review concludes with an outlook, including the new ELENA extension to the antiproton decelerator facility at CERN, together with summaries of how we envisage the major threads of antihydrogen physics will progress in the coming years

Competing charge transfer pathways at the photosystem II-electrode interface.

The integration of the water-oxidation enzyme photosystem II (PSII) into electrodes allows the electrons extracted from water oxidation to be harnessed for enzyme characterization and to drive novel endergonic reactions. However, PSII continues to underperform in integrated photoelectrochemical systems despite extensive optimization efforts. Here we carried out protein-film photoelectrochemistry using spinach and Thermosynechococcus elongatus PSII, and we identified a competing charge transfer pathway at the enzyme-electrode interface that short-circuits the known water-oxidation pathway. This undesirable pathway occurs as a result of photo-induced O2 reduction occurring at the chlorophyll pigments and is promoted by the embedment of PSII in an electron-conducting fullerene matrix, a common strategy for enzyme immobilization. Anaerobicity helps to recover the PSII photoresponse and unmasks the onset potentials relating to the QA/QB charge transfer process. These findings impart a fuller understanding of the charge transfer pathways within PSII and at photosystem-electrode interfaces, which will lead to more rational design of pigment-containing photoelectrodes in general.This work was supported by the U.K. Engineering and Physical Sciences Research Council (EP/H00338X/2 to E. Reisner), the U.K. Biology and Biotechnological Sciences Research Council (BB/K010220/1 to E. Reisner), a Marie Curie International Incoming Fellowship (PIIF-GA-2012-328085 RPSII to J.J.Z.). N.P. was supported by the Winton Fund for the Physics of Sustainability. E. Romero. and R.v.G. were supported by the VU University Amsterdam, the Laserlab-Europe Consortium, the TOP grant (700.58.305) from the Foundation of Chemical Sciences part of NWO, the Advanced Investigator grant (267333, PHOTPROT) from the European Research Council, and the EU FP7 project PAPETS (GA 323901). R.v.G. gratefully acknowledges his `Academy Professor' grant from the Royal Netherlands Academy of Arts and Sciences (KNAW). We would also like to thank Miss Katharina Brinkert and Prof A. William Rutherford for a sample of T. elongatus PSII, and H. v. Roon for preparation of the spinach PSII samples