Chemistry and analysis of HNE and other prominent carbonyl-containing lipid oxidation compounds

Publication date: Available online 10 February 2017
Source:Free Radical Biology and Medicine
Author(s): Bebiana C. Sousa, Andrew R. Pitt, Corinne M. Spickett
The process of lipid oxidation generates a diverse array of small aldehydes and carbonyl-containing compounds, which may occur in free form or esterified within phospholipids and cholesterol esters. These aldehydes mostly result from fragmentation of fatty acyl chains following radical oxidation, and the products can be subdivided into alkanals, alkenals (usually α,β-unsaturated), γ-substituted alkenals and bis-aldehydes. Isolevuglandins are non-fragmented di-carbonyl compounds derived from H2-isoprostanes, and oxidation of the ω−3-fatty acid docosahexenoic acid yield analogous 22 carbon neuroketals. Non-radical oxidation by hypochlorous acid can generate α-chlorofatty aldehydes from plasmenyl phospholipids. Most of these compounds are reactive and have generally been considered as toxic products of a deleterious process. The reactivity is especially high for the α,β-unsaturated alkenals, such as acrolein and crotonaldehyde, and for γ-substituted alkenals, of which 4-hydroxy-2-nonenal and 4-oxo-2-nonenal are best known. Nevertheless, in recent years several previously neglected aldehydes have been investigated and also found to have significant reactivity and biological effects; notable examples are 4-hydroxy-2-hexenal and 4-hydroxy-dodecadienal. This has led to substantial interest in the biological effects of all of these lipid oxidation products and their roles in disease, including proposals that HNE is a second messenger or signalling molecule. However, it is becoming clear that many of the effects elicited by these compounds relate to their propensity for forming adducts with nucleophilic groups on proteins, DNA and specific phospholipids. This emphasizes the need for good analytical methods, not just for free lipid oxidation products but also for the resulting adducts with biomolecules. The most informative methods are those utilizing HPLC separations and mass spectrometry, although analysis of the wide variety of possible adducts is very challenging. Nevertheless, evidence for the occurrence of lipid-derived aldehyde adducts in biological and clinical samples is building, and offers an exciting area of future research.

Graphical abstract

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REAL-TIME QUANTIFICATION OF SUBCELLULAR H202 AND GLUTATHIONE REDOX POTENTIAL IN LIVING CARDIOVASCULAR TISSUES

Publication date: Available online 10 February 2017
Source:Free Radical Biology and Medicine
Author(s): Emiliano Panieri, Carlo Millia, Massimo M. Santoro
Detecting and measuring the dynamic redox events that occur in vivo is a prerequisite for understanding the impact of oxidants and redox events in normal and pathological conditions. These aspects are particularly relevant in cardiovascular tissues wherein alterations of the redox balance are associated with stroke, aging, and pharmacological intervention. An ambiguous aspect of redox biology is how redox events occur in subcellular organelles including mitochondria, and nuclei. Genetically-encoded Rogfp2 fluorescent probes have become powerful tools for real-time detection of redox events. These probes detect hydrogen peroxide (H2O2) levels and glutathione redox potential (EGSH), both with high spatiotemporal resolution. By generating novel transgenic (Tg) zebrafish lines that express compartment-specific Rogfp2-Orp1 and Grx1-Rogfp2 sensors we analyzed cytosolic, mitochondrial, and the nuclear redox state of endothelial cells and cardiomyocytes of living zebrafish embryos. We provide evidence for the usefulness of these Tg lines for pharmacological compounds screening by addressing the blocking of pentose phosphate pathways (PPP) and glutathione synthesis, thus altering subcellular redox state in vivo. Rogfp2-based transgenic zebrafish lines represent valuable tools to characterize the impact of redox changes in living tissues and offer new opportunities for studying metabolic driven antioxidant response in biomedical research.

Graphical abstract

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Hypotensive and vasorelaxant effect of Diapocynin in normotensive rats

Publication date: Available online 10 February 2017
Source:Free Radical Biology and Medicine
Author(s): Simone R. Potje, Jéssica A. Troiano, Murilo E. Graton, Valdecir F. Ximenes, Ana Claúdia M.S. Nakamune, Cristina Antoniali
Nicotinamide adenine dinucleotide phosphate oxidase (NAD(P)H-oxidase) is a multicomponent enzyme system that generates superoxide anion by one-electron reduction of molecular oxygen and represents the major source of reactive oxygen species (ROS) in the vascular cells. Apocynin has been extensively used as an inhibitor of NADPH oxidase (NOX) in phagocytic cells and as an antioxidant in non-phagocytic cells. In phagocytes cells, due to the presence of myeloperoxidase, apocynin can be the converted to diapocynin, which is supposed to be the active form of this phytochemical. Moreover, apocynin was shown to induce hypotension and vasodilatation in many experimental animal models. However, there are no studies showing the effects of diapocynin on blood pressure or in vascular cells. In this present study, we used chemically synthesized diapocynin and analyzed its antioxidant capacity, effect on blood pressure and vascular reactivity. Moreover, it was evaluated the levels of nitric oxide (NO), ROS and calcium in aortic endothelial cells stimulated by diapocynin. All results were compared to apocynin. We found that diapocynin showed higher antioxidant capacity than apocynin. Apocynin and diapocynin, promoted hypotensive effects without changing the heart rate, however the effects of diapocynin were reversed faster than the effects of apocynin, which was long lasting. Diapocynin and apocynin induced endothelium dependent and independent vasodilatation, but diapocynin was less potent than apocynin regarding the capacity of induction of vasodilatation in mesenteric resistance arteries and aorta from Wistar rats. The relaxation induced by apocynin or diapocynin involves sGC and potassium channels in vascular smooth muscle cells and NOS participates of relaxation induced by apocynin or diapocynin in intact mesenteric rings. Apocynin and diapocynin increased NO and decreased ROS levels in endothelial cells, however diapocynin did not alter calcium levels in these cells. In conclusion, these results demonstrated that, similarly to apocynin, diapocynin also induces hypotensive and vasodilator effects in rats and vascular endothelium improves the diapocynin vasodilator effects by increases NO bioavailability.

Graphical abstract

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Risk of autoimmune diseases and human papilloma virus (HPV) vaccines: Six years of case-referent surveillance

Publication date: Available online 9 February 2017
Source:Journal of Autoimmunity
Author(s): Lamiae Grimaldi-Bensouda, Michel Rossignol, Isabelle Koné-Paut, Alain Krivitzky, Christine Lebrun-Frenay, Johanna Clet, David Brassat, Caroline Papeix, Marc Nicolino, Pierre-Yves Benhamou, Olivier Fain, Nathalie Costedoat-Chalumeau, Marie-France Courcoux, Jean-François Viallard, Bertrand Godeau, Thomas Papo, Patrick Vermersch, Isabelle Bourgault-Villada, Gerard Breart, Lucien Abenhaim
BackgroundSafety of HPV vaccines is still in question due to reports of autoimmune diseases (ADs) following HPV immunization.ObjectivesTo assess the risk of ADs associated with HPV vaccination of female adolescents/young adults in France.MethodsSystematic prospective case-referent study conducted to assess the risks associated with real-life use of HPV vaccines. Cases were female 11–25 years old with incident ADs [central demyelination/multiple sclerosis (CD/MS), connective tissue disease (CTD), Guillain-Barré syndrome (GBS), type-1 diabetes (T1D), autoimmune thyroiditis (AT), and idiopathic thrombocytopenic purpura (ITP)]. Cases were consecutively and prospectively identified at specialized centers across France (2008–2014) and individually matched by age and place of residence to referents recruited in general practice. Risk was computed using multivariate conditional logistic regression models adjusted for family history of ADs, living in France (north/south), co-medications and co-vaccinations.ResultsWith a total of 478 definite cases matched to 1869 referents, all ADs combined were negatively associated to HPV vaccination with an adjusted odds ratio of 0.58 (95% confidence interval: 0.41–0.83). Similar results were obtained for CD/MS, AT, CT, and T1D, the last two not reaching statistical significance. No association was found for ITP and GBS. Sensitivity analyses combining definite and possible cases with secondary time window showed similar results.ConclusionExposure to HPV vaccines was not associated with an increased risk of ADs within the time period studied. Results were robust to case definitions and time windows of exposure. Continued active surveillance is needed to confirm this finding for individual ADs.



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Cross-sectional analysis of universal vitamin D supplementation in former East Germany during the first year of life

Journal Name: Journal of Pediatric Endocrinology and Metabolism
Issue: Ahead of print


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Association between CSF biomarkers, hippocampal volume and cognitive function in patients with amnestic mild cognitive impairment (MCI)

Publication date: May 2017
Source:Neurobiology of Aging, Volume 53
Author(s): Pradeep J. Nathan, Yen Ying Lim, Rosemary Abbott, Samantha Galluzzi, Moira Marizzoni, Claudio Babiloni, Diego Albani, David Bartres-Faz, Mira Didic, Lucia Farotti, Lucilla Parnetti, Nicola Salvadori, Bernhard W. Müller, Gianluigi Forloni, Nicola Girtler, Tilman Hensch, Jorge Jovicich, Annebet Leeuwis, Camillo Marra, José Luis Molinuevo, Flavio Nobili, Jeremie Pariente, Pierre Payoux, Jean-Philippe Ranjeva, Elena Rolandi, Paolo Maria Rossini, Peter Schönknecht, Andrea Soricelli, Magda Tsolaki, Pieter Jelle Visser, Jens Wiltfang, Jill C. Richardson, Régis Bordet, Olivier Blin, Giovanni B. Frisoni
Few studies have examined the relationship between CSF and structural biomarkers, and cognitive function in MCI. We examined the relationship between cognitive function, hippocampal volume and cerebrospinal fluid (CSF) Aβ42 and tau in 145 patients with MCI. Patients were assessed on cognitive tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB), the Geriatric Depression Scale and the Functional Activities Questionnaire. Hippocampal volume was measured using magnetic resonance imaging (MRI), and CSF markers of Aβ42, tau and p-tau181 were also measured. Worse performance on a wide range of memory and sustained attention tasks were associated with reduced hippocampal volume, higher CSF tau and p-tau181 and increased tau/Aβ42 ratio. Memory tasks were also associated with lower ability to conduct functional activities of daily living, providing a link between AD biomarkers, memory performance and functional outcome. These results suggest that biomarkers of Aβ and tau are strongly related to cognitive performance as assessed by the CANTAB, and have implications for the early detection and characterization of incipient AD.



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Intrafamilial variable phenotype including Corticobasal Syndrome in a family with p.P301L mutation in the MAPT gene: first report in South America

Publication date: Available online 10 February 2017
Source:Neurobiology of Aging
Author(s): Emilia M. Gatto, Ricardo F. Allegri, Gustavo Da Prat, Patricio Chrem Mendez, David S. Hanna, Michael O. Dorschner, Ezequiel I. Surace, Cyrus P. Zabetian, Ignacio F. Mata
Frontotemporal lobar degeneration (FTLD) is a neuropathological disorder that causes a variety of clinical syndromes including fronto-temporal dementia (FTD), progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). FTD associated with parkinsonism occurs frequently as a result of mutations in the C9orf72 gene and also in the genes coding for the protein associated with microtubule tau (MAPT) and progranulin (GRN) on chromosome 17 (FTDP-17).Herein we report an Argentinean family, of Basque ancestry, with an extensive family history of behavioral variant of FTD (bvFTD). Twenty one members over 6 generations composed the pedigree. An extensive neurological and neurocognitive examination was performed on 2 symptomatic individuals and 3 non-symptomatic individuals. Two different phenotypes were identified among affected members, CBS in the proband and FTD in his brother.DNA was extracted from blood for these five individuals and whole-exome sequencing (WES) was performed on 3 of them followed by Sanger sequencing of candidate genes on the other 2. In both affected individuals a missense mutation (p.P301L; rs63751273) in exon 10 of the MAPT gene (chr17q21.3) was identified. Among MAPT mutations, p.P301L is the most frequently associated to different phenotypes: a) aggressive, symmetrical and early-onset Parkinsonism; b) late parkinsonism associated with FTD and c) PSP but only exceptionally it is reported associated to CBS. This is the first report of the occurrence of the p.P301L-MAPT mutation in South America and supports the marked phenotypic heterogeneity among members of the same family as previously reported.



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Non-amyloidogenic processing of amyloid beta precursor protein is associated with retinal function improvement in aging male APPswe/PS1ΔE9 mice

Publication date: Available online 10 February 2017
Source:Neurobiology of Aging
Author(s): Sandrine Joly, Simon Lamoureux, Vincent Pernet
Vision declines during normal aging and in Alzheimer's disease (AD). Although the toxic role of amyloid beta (Aβ) has been established in AD pathogenesis, its influence on the aging retina is unclear. Using APPswe/PS1ΔE9 transgenic (TG) mice, a classical AD model, the retinal cell function and survival was assessed by electroretinogram (ERG) recordings and immunofluorescent stainings. Strikingly, photopic ERG measurements revealed that the retinal response mediated by cones was preserved in aging TG mice relative to WT controls. In contrast to the cortex, the expression of mutated APPswe and PS1ΔE9 did not allow to detect Aβ or amyloid plaques in 13-month old male TG retinae. In addition, the CTFβ/CTFα ratio was significantly lower in retinal samples than in cortical extracts, suggesting that the non-amyloidogenic pathway may endogenously limit Aβ formation in the retina of male mice. Collectively, our data suggest that retinal-specific processing of amyloid may confer protection against AD and selectively preserve cone-dependent vision during aging.



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COx-free hydrogen generation via decomposition of ammonia over copper and zinc-based catalysts

Publication date: 15 May 2017
Source:Fuel, Volume 196
Author(s): Venkata D.B.C. Dasireddy, Blaž Likozar
Production of hydrogen without any carbon dioxide or monoxide is of utmost importance for the chemical energy storage and conversion in a future low-carbon economy. Alumina-supported copper and Cu/Zn/Al2O3 catalysts were prepared by incipient wetness- and ultrasonic impregnation, while Zn/Al2O3 catalysts were also prepared to compare the effect of Zn. The characterisation of catalysts was carried out by N2 physisorption, XRD, H2-TPR, N2O chemisorption, NH3-TPD, CO2-TPD, H2-TPD, XPS and TEM. Catalysts prepared via ultrasonic impregnation showed a high metal dispersion and a small crystallite size, whereas Lewis acidic and basic sites were predominant on all catalysts, while the acid–base strength was strongly influenced by the presence of zinc in the case of Cu/Zn/Al2O3 catalysts. A high catalytic activity, reflected through the almost total conversion of ammonia at 600°C with the H2 production rate of 36.2mmolg⁻¹min⁻¹, was achieved over Cu/Zn/Al2O3 catalyst, prepared by ultrasonic impregnation. The dispersion of metal and its acidic or basic nature played an important role, even more so than the presence of the two or three potentially synergistic metals on the surface of a catalyst. Under the applied reaction conditions, the catalysts showed an excellent stability for more than 100h.

Graphical abstract

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Bedload as an indicator of heavy metal contamination in a Brazilian anthropized watershed

Publication date: June 2017
Source:CATENA, Volume 153
Author(s): Yuri Jacques Agra Bezerra da Silva, José Ramon Barros Cantalice, Clístenes Williams Araújo do Nascimento, Vijay P. Singh, Ygor Jacques Agra Bezerra da Silva, Cinthia Maria Cordeiro Atanázio Cruz Silva, Michelangelo de Oliveira Silva, Sérgio M.S. Guerra
Heavy metal contamination has long been a water quality concern worldwide. Most studies have focused on heavy metal concentration in water through suspended sediment and bottom sediment; however, the concentration transported by river-bottom sediment, known as bedload, has not been taken into account. In order to fill this gap, this study aimed to determine the concentration of Hg, Pb, Cd, Ni, Cu, Cr, Zn, As, Fe and Mn in bedload of Ipojuca River which is an environmentally impacted river in Brazil. The use of bedload in heavy metal contamination studies raises the following question: Is the bedload an adequate indicator of heavy metal contamination? To answer this question, sediment contamination assessment was performed using sediment contamination indices, principal component analysis, and comparison with background values and sediment quality guidelines (SQGs). Comparing with sediment quality guidelines, the Probable Effect Level (PEL) and Threshold Effect Level (TEL) seem to underestimate the harmful effect on sediment-dwelling organisms, being essential either to calibrate the SQGs for site specific conditions or develop site specific guidelines. The pollution load index (PLI) indicated that the upstream and downstream sites were not polluted and polluted, respectively. Principal component analysis explained roughly 91% and 81% of the total variance in heavy metal contamination upstream and downstream, respectively, and distinguished natural and anthropogenic contributions in Ipojuca River. Multiple lines of evidence suggested that heavy metal concentrations in bedload were an adequate and feasible indicator of anthropogenic impacts.



http://ift.tt/2kY00TG

Complement’s hidden arsenal: New insights and novel functions inside the cell

Publication date: Available online 10 February 2017
Source:Molecular Immunology
Author(s): M. Kathryn Liszewski, Michelle Elvington, Hrishikesh S. Kulkarni, John P. Atkinson
A key component of both innate and adaptive immunity, new understandings of the complement system are expanding its roles beyond that traditionally appreciated. Evidence is accumulating that complement has an intracellular arsenal of components that provide not only immune defense, but also assist in key interactions for host cell functions. Although early work has primarily centered on T cells, the intracellular complement system likely functions in many if not most cells of the body. Some of these functions may trace their origins to the primitive complement system that began as a primeval form of C3 likely tasked for protection from intracellular pathogen invasion. This later expanded to include extracellular defense as C3 became a secreted protein to patrol the vasculature. Other components were added to the growing system including regulators to protect host cells from the indiscriminate effects of this potent system. Contemporary cells may retain some of these vestigial remnants. We now know that a) C3 serves as a damage-associated molecular pattern (in particular by coating pathogens that translocate into cells), b) most cells store C3 and recycle C3(H2O) for immediate use, and c) C3 assists in cellular survival and metabolic reprogramming. Other components also are part of this hidden arsenal including C5, properdin, factors H and B, and complement receptors. Importantly, better definition of the intracellular complement system may translate into new target discovery to assist in creating the next generation of complement therapeutics.



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Enhanced biodegradation of low and high-density polyethylene by novel bacterial consortia formulated from plastic-contaminated cow dung under thermophilic conditions

Abstract

The current study aimed to devise eco-friendly, safe, and cost-effective strategies for enhanced degradation of low- and high-density polyethylene (LDPE and HDPE) using newly formulated thermophilic microbial consortia from cow dung and to assess the biodegradation end products. The plastic-degrading bacteria from cow dung samples gathered from highly plastic-acclimated environments were enriched by standard protocols. The degradation ability was comprehended by zone of clearance method, and the percentage of degradation was monitored by weight reduction process. The best isolates were characterized by standard microbiological and molecular biology protocols. The best isolates were employed to form several combinations of microbial consortia, and the degradation end products were analyzed. The stability of 16S ribosomal DNA (rDNA) was predicted by bioinformatics approach. This study identified 75 ± 2, 55 ± 2, 60 ± 3, and 43 ± 3% degradation for LDPE strips, pellets, HDPE strips, and pellets, respectively, for a period of 120 days (p < 0.05) at 55 °C by the formulated consortia of IS1-IS4, and the degradation efficiency was found to be better in comparison with other formulations. The end product analysis by Fourier transform infrared, scanning electron microscopy, energy-dispersive spectroscopy, and nuclear magnetic resonance showed major structural changes and formation of bacterial biofilm on plastic surfaces. These novel isolates were designated as Bacillus vallismortis bt-dsce01, Psuedomonas protegens bt-dsce02, Stenotrophomonas sp. bt-dsce03, and Paenibacillus sp.bt-dsce04 by 16S rDNA sequencing and suggested good gene stability with minimum Gibb's free energy. Therefore, this study imparts substantial information regarding the utilization of these thermophilic microbial consortia from cow dung for rapid polyethylene removal.

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Quantification of the fate of mesotrione applied alone or in a herbicide mixture in two Brazilian arable soils

Abstract

The effects of mesotrione, S-metolachlor, and terbuthylazine, applied in mixture, on soil biodegradation remain insufficiently researched. However, herbicide mixtures have been a common practice in agricultural systems in the last years. Understanding the fate of soil-applied herbicides may help on planning weed management tactics towards more sustainable and efficient weed control. Therefore, this study evaluated the fate of mesotrione alone and in mixture with S-metolachlor and terbuthylazine when applied to two contrasting arable Brazilian soils. Mineralization and degradation experiments were conducted using ¹⁴C-mesotrione alone or in mixture. From the 49-day laboratory incubation data, increased mineralization half-life of mesotrione was observed for the mixture of herbicides, ranging from a 4-day increase for the sandy loam soil to a 1-day increase in the sandy clay texture soils. Mesotrione degradation rate had a twofold increase in the sandy loam compared to the sandy clay soil. Two metabolites can be identified from mesotrione degradation, 4-methyl-sulfonyl-2-nitrobenzoic acid (MNBA) and 2-amino-4-methylsulfonyl benzoic acid (AMBA). Indices for the score of ubiquity in groundwater indicated mesotrione possesses leaching potential for both soils. Applying mesotrione alone or in mixture did not influence the amount of bound residues from mesotrione. However, mesotrione degradation rate was influenced by soil texture regardless if applied alone or in mixture. Mesotrione biotransformation was relatively quick, indicating that this herbicide has low persistence and, consequently, low residual effect on crops and weeds when present in similar soils to this present study.

http://ift.tt/2kdSyzt

Concentrations of some heavy metals in underground water samples from a Nigerian crude oil producing community

Abstract

Pollution due to oil exploration activities in the Niger Delta region of Nigeria and government under-investments in potable water infrastructure has led to the dependence of the population on personal boreholes. Yet, there are little quality or surveillance reports on such waters. The concentrations of heavy metals in underground water samples from an oil producing area, Umuebulu, in the Niger Delta were therefore investigated. Water samples were collected from three test points, each approximately 300 m from (1) wellhead area (WHA), (2) flare area (FA) and (3) effluent discharge area (EDA), and one control point located 10 km away from any oil-related activity. The concentrations of lead, arsenic and cadmium were determined in the samples using atomic absorption spectrophotometry. All three heavy metals were present in the test, and control water samples at concentrations significantly (P < 0.05) exceeding the maximum contaminant levels recommended by the World Health Organization. The total hazard index of the water samples showed that their consumption constituted significant health risks in the order EDA > FA > WHA > Control. Appropriate water treatment and surveillance is warranted and therefore recommended for underground water resources of the studied community.

http://ift.tt/2kch0G6

Successful TEVAR with a Through and Through Guidewire in an Extremely Tortuous Aorta

Publication date: Available online 10 February 2017
Source:European Journal of Vascular and Endovascular Surgery
Author(s): B. Fiorucci, N. Tsilimparis




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Calculating the incalculable. Optimal radioiodine dose in Graves’ hyperthyroidism

http://ift.tt/2kuIOln

Short-term UVB irradiation significantly increases vitamin D serum concentration in obese patients: a clinical pilot study

Abstract

Purpose

Deficiency of vitamin D is very common in obese people and treatment by oral supplementation is not effective in all patients. This exploratory pilot study investigated the influence of different doses of short-term ultraviolet B irradiation on serum 25-hydroxyvitamin-D₃ (25D) and 1,25-dihydroxyvitamin-D₃ (1,25D) levels in obese compared to normal weight subjects and obese controls.

Methods

Participants with skin types II and III (Fitzpatrick skin classification) were assigned to six groups including four intervention groups receiving irradiation (three groups of obese and one group of normal weight subjects) and two control groups without treatment (obese and normal weight). Intervention groups received three sessions of whole body UVB irradiation of three different doses (cumulative doses over three sessions: 0.28, 0.70, 1.75 minimal erythema dose) within 1 week of intervention. Serum 25D and 1,25D were measured at baseline and after irradiation. Outcome differences between groups were analyzed using a linear model.

Results

Serum 25D levels increased significantly in obese (+23.6 and +26.7%, respectively, p = 0.01) and normal weight (+15.6%, p = 0.02) intervention groups who received medium and high doses of ultraviolet B irradiation compared to control groups (+3.5 and −4.0%, respectively, p = 1.0). The increase in obese patients was 51.4% greater compared to normal weight controls irradiated with equal ultraviolet B doses. Low-level ultraviolet irradiation did not result in a significant change in serum 25D (+7.0%, p = 0.61). We did not detect any significant differences of 1,25D between groups (p = 0.25).

Conclusions

The current study indicates that short-term ultraviolet B irradiation increases 25D levels in obese patients.

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CD8+ T Cells Orchestrate pDC-XCR1+ Dendritic Cell Spatial and Functional Cooperativity to Optimize Priming

Publication date: Available online 9 February 2017
Source:Immunity
Author(s): Anna Brewitz, Sarah Eickhoff, Sabrina Dähling, Thomas Quast, Sammy Bedoui, Richard A. Kroczek, Christian Kurts, Natalio Garbi, Winfried Barchet, Matteo Iannacone, Frederick Klauschen, Waldemar Kolanus, Tsuneyasu Kaisho, Marco Colonna, Ronald N. Germain, Wolfgang Kastenmüller
Adaptive cellular immunity is initiated by antigen-specific interactions between T lymphocytes and dendritic cells (DCs). Plasmacytoid DCs (pDCs) support antiviral immunity by linking innate and adaptive immune responses. Here we examined pDC spatiotemporal dynamics during viral infection to uncover when, where, and how they exert their functions. We found that pDCs accumulated at sites of CD8⁺ T cell antigen-driven activation in a CCR5-dependent fashion. Furthermore, activated CD8⁺ T cells orchestrated the local recruitment of lymph node-resident XCR1 chemokine receptor-expressing DCs via secretion of the XCL1 chemokine. Functionally, this CD8⁺ T cell-mediated reorganization of the local DC network allowed for the interaction and cooperation of pDCs and XCR1⁺ DCs, thereby optimizing XCR1⁺ DC maturation and cross-presentation. These data support a model in which CD8⁺ T cells upon activation create their own optimal priming microenvironment by recruiting additional DC subsets to the site of initial antigen recognition.

Graphical abstract

Teaser

pDCs and XCR1⁺ dendritic cells are critical for the generation of antiviral CD8⁺ T cell responses. Brewitz and colleagues demonstrate that primed CD8⁺ T cells reorganize the intranodal dendritic cell network to optimize pDC and XCR1⁺ DC cooperativity and thereby enhance CD8⁺ T cell immunity.


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Feasibility of Patient Reporting of Symptomatic Adverse Events via the PRO-CTCAE in a Chemoradiotherapy Cooperative Group Multicenter Clinical Trial

Publication date: Available online 10 February 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Ethan Basch, Stephanie L. Pugh, Amylou C. Dueck, Sandra A. Mitchell, Lawrence Berk, Shannon Fogh, Lauren J. Rogak, Marcha Gatewood, Bryce B. Reeve, Tito R. Mendoza, Ann O'Mara, Andrea Denicoff, Lori Minasian, Antonia V. Bennett, Ann Setser, Deborah Schrag, Kevin Roof, Joan K. Moore, Thomas Gergel, Kevin Stephans, Andreas Rimner, Albert DeNittis, Deborah Watkins Bruner
PurposeTo assess the feasibility of measuring symptomatic adverse events (AEs) in a multicenter clinical trial using the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE).Methods and MaterialsPatients enrolled in Trial XXXX (XXXX) were asked to self-report 53 PRO-CTCAE items representing 30 symptomatic AEs at 6 time points (baseline; weekly x4 during treatment; 12-weeks post-treatment). Reporting was conducted via wireless tablet computers in clinic waiting areas. Compliance was defined as the proportion of visits when an expected PRO-CTCAE assessment was completed.ResultsAmong 226 study sites participating in Trial XXXX, 100% completed 35-minute PRO-CTCAE training for clinical research associates (CRAs); 80 sites enrolled patients of which 34 (43%) required tablet computers to be provided. All 152 patients in Trial XXXX agreed to self-report using the PRO-CTCAE (median age 66; 47% female; 84% white). Median time for CRAs to learn the system was 60 minutes (range 30-240), and median time for CRAs to teach a patient to self-report was 10 minutes (range 2-60). Compliance was high, particularly during active treatment when patients self-reported at 86% of expected time points, although compliance was lower post-treatment (72%). Common reasons for non-compliance were institutional errors such as forgetting to provide computers to participants; patients missing clinic visits; internet connectivity; and patients feeling "too sick".ConclusionsMost patients enrolled in a multicenter chemoradiotherapy trial were willing and able to self-report symptomatic adverse events at visits using tablet computers. Minimal effort was required by local site staff to support this system. The observed causes of missing data may be obviated by allowing patients to self-report electronically between-visits, and by employing central compliance monitoring. These approaches are being incorporated into ongoing studies.

Teaser

The Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) was developed by the National Cancer Institute to enable patient-reporting of toxicities in clinical research. To assess feasibility of implementation, PRO-CTCAE was integrated into an NRG Oncology trial. During treatment, patients reported via tablet computers at 86% of visits. Reasons for missing reports included staff errors, missed appointments, and internet connectivity. Strategies to address these reasons are being assessed in ongoing studies.


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Direct access: how is it working?

British Dental Journal 222, 191 (2017). doi:10.1038/sj.bdj.2017.123

Authors: S. Turner & M. Ross

http://ift.tt/2lssrtD