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  • Wiley-Blackwell  (474,677)
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  • 1
    Call number: ALLG-BERUF-Q180:82
    Keywords: Science / Vocational guidance ; Communication in science ; Research ; Technical writing ; Scholarly publishing
    Abstract: "True academic success for a medical professional is multifaceted; one should have a clear and correct definition of success in order to proceed in the right direction. In establishing a successful career, communication skills and networking know-how are as important as having sufficient clinical knowledge and being capable of conducting research and writing scientific papers. Therefore, we are going to emphasize in the book that to be successful, a medical student/resident should have good communication skills, sound clinical judgment, enough knowledge of research methodology and good writing skills. We believe that for achieving this, students/residents need to have comprehensive guidelines to address each of these aspects. We believe this book has the potential to inspire many students/residents and physicians and will be well-received by the academic community"--
    Pages: xliii, 742 p. : ill.
    Edition: First edition.
    ISBN: 9781118907429
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  • 2
    Publication Date: 2018-03-06
    Description: Immunotherapy is revolutionizing cancer treatment and has shown success in particular for tumors with a high mutational load. These effects have been linked to neo-antigens derived from patient-specific mutations. To expand efficacious immunotherapy approaches to the vast majority of tumor types and patient populations carrying only a few mutations and maybe not a single presented neoepitope, it is necessary to expand the target space to non-mutated cancer-associated antigens. Mass spectrometry enables the direct and unbiased discovery and selection of tumor-specific HLA peptides that can be used to define targets for immunotherapy. Combining these targets into a warehouse allows for multi-target therapy and accelerated clinical application. For precise personalization aimed at optimally ensuring treatment efficacy and safety, it is necessary to assess the presence of the target on each individual patient's tumor. Here we show how LC-MS paired with gene expression data was used to define mRNA biomarkers currently being used as diagnostic test IMA_Detect TM for patient inclusion and personalized target selection within two clinical trials (NCT02876510, NCT03247309). Thus, we present a way how to translate HLA peptide presentation into gene expression thresholds for companion diagnostics in immunotherapy considering the peptide-specific correlation to its encoding mRNA. This article is protected by copyright. All rights reserved
    Print ISSN: 1615-9853
    Electronic ISSN: 1615-9861
    Topics: Medicine
    Published by Wiley-Blackwell
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  • 3
    Publication Date: 2018-03-06
    Description: Immunopeptidomes promise novel surface markers as ideal immunotherapy targets, but their characterization by mass spectrometry (MS) remains challenging. Until recently, cell numbers exceeding 10 9 were needed to survey thousands of HLA ligands. Such limited analytical sensitivity has historically constrained the types of clinical specimens that can be evaluated to cell cultures or bulk tissues. Measuring immunopeptidomes from purified cell subpopulations would be preferable for many applications, particularly those evaluating rare, primary hematopoietic cell lineages. Here, we test the feasibility of immunopeptidome profiling from limited numbers of primary purified human regulatory T cells (T Reg ), conventional T cells (T conv ) and activated T cells. The combined T-cell immunopeptide dataset reported here contains 13,804 unique HLA ligands derived from 5,049 proteins. Of these, more than 700 HLA ligands were derived from 82 proteins that we exclusively identified from T Reg -enriched cells. This study 1) demonstrates that primary, lineage-enriched T cell supbopulations recovered from single donors are compatible with immunopeptidome analysis; 2) presents new T Reg -biased ligand candidates; and 3) supports immunopeptidome surveys value for revealing T cell biology that may not be apparent from expression data alone. Taken together, these findings open up new avenues for targeting T Reg and abrogating their suppressive functions to treat cancer. This article is protected by copyright. All rights reserved
    Print ISSN: 1615-9853
    Electronic ISSN: 1615-9861
    Topics: Medicine
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  • 4
    Publication Date: 2018-03-06
    Description: When devising a course of treatment for a patient, doctors often have little quantitative evidence on which to base their decisions, beyond their medical education and published clinical trials. Stanford Health Care alone has millions of electronic medical records that are only just recently being leveraged to inform better treatment recommendations. These data present a unique challenge because they are high dimensional and observational. Our goal is to make personalized treatment recommendations based on the outcomes for past patients similar to a new patient. We propose and analyze 3 methods for estimating heterogeneous treatment effects using observational data. Our methods perform well in simulations using a wide variety of treatment effect functions, and we present results of applying the 2 most promising methods to data from The SPRINT Data Analysis Challenge, from a large randomized trial of a treatment for high blood pressure.
    Print ISSN: 0277-6715
    Electronic ISSN: 1097-0258
    Topics: Mathematics , Medicine
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  • 5
    Publication Date: 2018-03-06
    Print ISSN: 0277-6715
    Electronic ISSN: 1097-0258
    Topics: Mathematics , Medicine
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  • 6
    Publication Date: 2018-03-06
    Description: Propensity score methods are increasingly being used to estimate the effects of treatments and exposures when using observational data. The propensity score was initially developed for use with binary exposures. The generalized propensity score (GPS) is an extension of the propensity score for use with quantitative or continuous exposures (eg, dose or quantity of medication, income, or years of education). We used Monte Carlo simulations to examine the performance of different methods of using the GPS to estimate the effect of continuous exposures on binary outcomes. We examined covariate adjustment using the GPS and weighting using weights based on the inverse of the GPS. We examined both the use of ordinary least squares to estimate the propensity function and the use of the covariate balancing propensity score algorithm. The use of methods based on the GPS was compared with the use of G-computation. All methods resulted in essentially unbiased estimation of the population dose-response function. However, GPS-based weighting tended to result in estimates that displayed greater variability and had higher mean squared error when the magnitude of confounding was strong. Of the methods based on the GPS, covariate adjustment using the GPS tended to result in estimates with lower variability and mean squared error when the magnitude of confounding was strong. We illustrate the application of these methods by estimating the effect of average neighborhood income on the probability of death within 1 year of hospitalization for an acute myocardial infarction.
    Print ISSN: 0277-6715
    Electronic ISSN: 1097-0258
    Topics: Mathematics , Medicine
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  • 7
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    Wiley-Blackwell
    Publication Date: 2018-03-06
    Description: No abstract is available for this article.
    Print ISSN: 0277-6715
    Electronic ISSN: 1097-0258
    Topics: Mathematics , Medicine
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  • 8
    Publication Date: 2018-03-07
    Description: In boron neutron capture therapy (BNCT), 10 B-4-borono-L-phenylalanine (BPA) is commonly used as a 10 B carrier. Positron emission tomography using 4-borono-2- 18 F-fluoro-phenylalanine ( 18 F-FBPA PET) has been performed to estimate boron concentration and predict the therapeutic effects of BNCT; however, the association between tumor uptake of 18 F-FBPA and boron concentration in tumors remains unclear. The present study investigated the transport mechanism of 18 F-FBPA and BPA, and evaluated the utility of 18 F-FBPA PET in predicting boron concentration in tumors. The transporter assay revealed that 2-aminobicyclo-(2.2.1)-heptane-2-carboxylic acid, an inhibitor of the L-type amino acid transporter, significantly inhibited 18 F-FBPA and 14 C-BPA uptake in FaDu and LN-229 human cancer cells. 18 F-FBPA uptake strongly correlated with 14 C-BPA uptake in seven human tumor cell lines (r = 0.93; p 〈0.01). PET experiments demonstrated that tumor uptake of 18 F-FBPA was independent of the administration method, and uptake of 18 F-FBPA by bolus injection correlated well with BPA uptake by continuous intravenous infusion. The results of this study revealed that evaluating tumor uptake of 18 F-FBPA by PET was useful for estimating 10 B concentration in tumors. This article is protected by copyright. All rights reserved.
    Topics: Medicine
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  • 9
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    Wiley-Blackwell
    Publication Date: 2018-03-07
    Description: Cover of this issue. Cladogran of taxa of microbiota in the mice in the model and Bifico group. See also Song et al. (pp. 666–677 of this issue).
    Topics: Medicine
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  • 10
    Publication Date: 2018-03-07
    Description: Taselisib is a potent and selective phosphatidylinositide 3-kinase (PI3K) inhibitor. This paper reports the first study of taselisib administration in Japanese patients. The aim of this two-stage, phase I, multicenter, open-label, dose-escalation study was to evaluate the safety, pharmacokinetics, and preliminary efficacy of taselisib as monotherapy in Japanese patients with advanced solid tumors (Stage 1), and as part of combination therapy in Japanese patients with hormone receptor (HR)-positive locally advanced or recurrent breast cancer (Stage 2). In Stage 1, oral taselisib tablets 2, 4, and 6 mg/day were administered in 28-day cycles. In Stage 2, successive cohorts of patients received oral taselisib tablets (2 or 4 mg/day) with intramuscular fulvestrant 500 mg. Nine and six patients were enrolled in Stage 1 and Stage 2, respectively. Taselisib was well tolerated. No dose-limiting toxicities were experienced in any cohort of patients and no deaths were observed. The most common treatment-related adverse events in Stage 1 and Stage 2 were rash (55.6%, 66.7%), diarrhea (44.4%, 66.7%), stomatitis (44.4%, 66.7%). Taselisib was rapidly absorbed after administration; its half-life was 12.9–32.0 hours in Stage 1 and 16.1–26.5 hours in Stage 2. Two patients achieved partial response (PR) and five patients had stable disease (SD) in Stage 1, and one patient had PR and five patients had SD in Stage 2. All patients with PR were positive for PIK3CA gene mutations. These preliminary data suggest that taselisib may be effective in patients with PIK3CA -mutated solid tumors or HR-positive advanced breast cancer. This article is protected by copyright. All rights reserved.
    Topics: Medicine
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  • 11
    Publication Date: 2018-03-07
    Description: Metastasis is the leading cause of cancer deaths. A tumor-supportive microenvironment, or premetastatic niche, at potential secondary tumor sites plays an important role in metastasis, especially in tumor cell colonization. Although a fibrotic milieu is known to promote tumorigenesis and metastasis, the underlying molecular contributors to this effect have remained unclear. Here we show that periostin, a component of the extracellular matrix that functions in tissue remodeling, has a key role in formation of a fibrotic environment that promotes tumor metastatic colonization. We found that periostin was widely expressed in fibrotic lesions of mice with bleomycin-induced lung fibrosis, and that up-regulation of periostin expression coincided with activation of myofibroblasts positive for α–smooth muscle actin. We established a lung metastasis model for B16 murine melanoma cells and showed that metastatic colonization of the lung by these cells was markedly promoted by bleomycin-induced lung fibrosis. Inhibition of periostin expression by intratracheal administration of an antisense oligonucleotide targeting periostin mRNA was found to suppress bleomycin-induced lung fibrosis and thereby to attenuate metastatic colonization of the lung by melanoma cells. Our results indicate that periostin is a key player in the development of bleomycin-induced fibrosis and consequent enhancement of tumor cell colonization in the lung, and they therefore implicate periostin as a potential target for prevention or treatment of lung metastasis. This article is protected by copyright. All rights reserved.
    Topics: Medicine
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  • 12
    Publication Date: 2018-03-07
    Description: Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of nodal peripheral T-cell lymphomas. Somatic RHOA mutations, most frequently found at the hotspot site c.50G〉T, p. Gly17Val (G17V RHOA mutation) are a genetic hallmark of AITL. Detection of the G17V RHOA mutations assists prompt and appropriate diagnosis of AITL. However, an optimal detection method for the G17V RHOA mutation remains to be elucidated. We compared the sensitivity and concordance of next generation sequencing (NGS), droplet digital PCR (ddPCR) and PNA-LNA clamp method for detecting the G17V RHOA mutations. The G17V RHOA mutations were identified in 27 of 67 (40.3%) PTCL samples using NGS. ddPCR and PNA-LNA clamp method both detected the G17V mutations in 4 samples in addition to those detected with NGS (31of 67, 46.3%). Additionally, variant allele frequencies with ddPCR and those with NGS showed high concordance ( P 〈0.001). Three other RHOA mutations involving the p.Gly17 position (c.[49G〉T;50G〉T], p.Gly17Leu in PTCL198; c.[50G〉T;51A〉C], p.Gly17Val in PTCL216; and c.50G〉A, p.Gly17Glu in PTCL223) were detected using NGS. These sequence changes could not appropriately be detected using the ddPCR assay and PNA-LNA clamp method although both indicated that the samples might have mutations. In total, 34 out of 67 PTCL samples (50.7%) had the RHOA mutations at the p.Gly17Val position. In conclusion, our results suggested that combination of ddPCR/PNA-LNA clamp methods and NGS are best feasible to assist the diagnosis of AITL by detecting the RHOA mutations at the p.Gly17 position. This article is protected by copyright. All rights reserved.
    Topics: Medicine
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  • 13
    Publication Date: 2018-03-07
    Description: River flow fluctuation has an important influence on riparian vegetation dynamics. A temporally segmented stochastic model focusing on a same-aged population is developed for the purpose of describing both spatial and temporal dynamics of riparian vegetation. In the model, the growth rate of population, rather than carrying capacity, is modeled as the random variable. This model has explicit physical meaning. The model deduces a process-based solution. From the solution process, the probability density of spatial distribution can be derived; therefore, the spatial distribution of population abundance can be described. The lifespan of a same-aged population and the age structure of the species-specific population can also be studied with the aid of this temporally segmented model. The influence of correlation time of river flow fluctuation is also quantified according to the model. The calibration of model parameters and model application are discussed. The model provides a computer-aided method to simulate and predict vegetation dynamics during river flow disturbances. Meanwhile, the model is open and allows for more accurate and concrete modeling of growth rate. Because of the Markov property involved in the process-based solution, the model also has the ability to deal with cases of nonstationary disturbances. The model provides a computer-aided method to simulate and predict vegetation dynamics during river flow disturbances. Meanwhile, the model is open and allows for more accurate and concrete modeling of growth rate and has the ability to deal with cases of nonstationary disturbances.
    Electronic ISSN: 2045-7758
    Topics: Biology
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  • 14
    Publication Date: 2018-03-07
    Description: Diet regulation behavior can mediate the consequences of imbalanced diets for animal well-being, particularly for captive species that have little dietary choice. Dasyurids (carnivorous marsupials) are of conservation concern in Australia, and many species are in captive breeding programmes. However, their nutrient targets and dietary regulation behaviors are poorly understood, a limitation that may decrease the breeding success and well-being of captive animals. We tested how dietary protein content influenced the intake and utilization of nutrients, physical activity, and body mass of fat-tailed dunnarts Sminthopsis crassicaudata . Twelve adult dunnarts from six sibling pairs (one female and one male per pair) were provided ad libitum access to three diets in a repeated measures design: cat food, cat food supplemented with raw lean beef (1:1), and cat food supplemented with cooked lean beef (1:1). Food intake, activity level, and fecal output were measured daily. Dunnarts significantly decreased food intake, increased protein digestion, and physical activity, but body mass was unchanged when on the high-protein diet compared to the normal cat food diet. These observations suggest a capacity of dunnarts to maintain constant body mass using a dynamic balance of feeding, digestion, and activity. We also found a significant effect of family, with differences between families as large as the difference between the diet treatments, suggesting a genetic component to diet selection. The nutrient regulation responses of dunnarts to high-protein diets and the strong family effects provide important messages for the management of populations of small carnivores, including the aspects of dietary manipulation and conservation of genetic diversity. When challenged with diets with different protein components, the small marsupial carnivore, Sminthopsis crassicaudata, moderated food intake and increased activity when on a high-protein diet, but body mass did not change. Surprisingly, there was a large effect of their genetic background on activity and food consumption; this effect was as large as the effect from the diets and sends a cautionary message about assumptions concerning food consumption in captive and wild animals.
    Electronic ISSN: 2045-7758
    Topics: Biology
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  • 15
    Publication Date: 2018-03-07
    Description: Southwest China is an important biodiversity hotspot. The interactions among the complex topography, climate change, and ecological factors in the dry-hot valley areas in southwest China may have profoundly affected the genetic structure of plant species in this region. In this study, we determined the effects of the Tanaka Line on genetic variation in the wild Bombax ceiba tree in southwest China. We sampled 224 individuals from 17 populations throughout the dry-hot valley regions. Six polymorphic expressed sequence tag–simple sequence repeat primers were employed to sequence the PCR products using the first-generation Sanger technique. The analysis based on population genetics suggested that B. ceiba exhibited a high level of gene diversity ( H E : 0.2377–0.4775; I : 0.3997–0.7848). The 17 populations were divided into two groups by cluster analysis, which corresponded to geographic characters on each side of the Tanaka Line. In addition, a Mantel test indicated that the phylogeographic structure among the populations could be fitted to the isolation-by-distance model ( r 2  = .2553, p  〈 .001). A barrier test indicated that there were obstacles among populations and between the two groups due to complex terrain isolation and geographic heterogeneity. We inferred that the Tanaka Line might have promoted the intraspecific phylogeographic subdivision and divergence of B. ceiba . These results provide new insights into the effects of the Tanaka Line on genetic isolation and population differentiation of plant species in southwest China. In the study, we used six pairs of EST-SSR primers to explore population structure and diversity of B .  cieba wild populations from both sides of Tanaka Line. Moreover, we used the Sanger sequencing of PCR products to make the results more accurate and reliable.
    Electronic ISSN: 2045-7758
    Topics: Biology
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  • 16
    Publication Date: 2018-03-07
    Description: Resource selection functions (RSFs) are tremendously valuable for ecologists and resource managers because they quantify spatial patterns in resource utilization by wildlife, thereby facilitating identification of critical habitat areas and characterizing specific habitat features that are selected or avoided. RSFs discriminate between known-use resource units (e.g., telemetry locations) and available (or randomly selected) resource units based on an array of environmental features, and in their standard form are performed using logistic regression. As generalized linear models, standard RSFs have some notable limitations, such as difficulties in accommodating nonlinear (e.g., humped or threshold) relationships and complex interactions. Increasingly, ecologists are using flexible machine-learning methods (e.g., random forests, neural networks) to overcome these limitations. Herein, we investigate the seasonal resource selection patterns of mule deer ( Odocoileus hemionus ) by comparing a logistic regression framework with random forest (RF), a popular machine-learning algorithm. Random forest (RF) models detected nonlinear relationships (e.g., optimal ranges for slope and elevation) and complex interactions which would have been very challenging to discover and characterize using standard model-based approaches. Compared with standard RSF models, RF models exhibited improved predictive skill, provided novel insights about resource selection patterns of mule deer, and, when projected across a relevant geographic space, manifested notable differences in predicted habitat suitability. We recommend that wildlife researchers harness the strengths of machine-learning tools like RF in addition to “classical” tools (e.g., mixed-effects logistic regression) for evaluating resource selection, especially in cases where extensive telemetry data sets are available. Resource selection functions (RSFs, which discriminate between used and available habitats on the basis of environmental features) are widely used by ecologists and resource managers but traditional approaches (generalized linear models) have limited power to detect and characterize nonlinear responses and complex interactions. Using a population of GPS-collared migratory mule deer in Nevada, USA, as a case study, we contrasted a classical RSF approach (mixed-effects logistic regression) with a more flexible machine-learning approach (random forest). The machine-learning approach provided important insights about seasonal resource selection patterns of mule deer that would have been difficult or impossible to achieve using classical RSF methods, leading us to conclude that machine-learning methods can complement and extend classical RSF approaches, especially in cases where extensive telemetry data sets are available.
    Electronic ISSN: 2045-7758
    Topics: Biology
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  • 17
    Publication Date: 2018-03-07
    Description: Passeriformes is the largest and most diverse avian order in the world and comprises the Passeri and Tyranni suborders. These suborders constitute a monophyletic group, but differ in their ecology and history of occupation of South America. We investigated the influence of biogeographic history on functional and phylogenetic diversities of Passeri and Tyranni in forest and savanna habitats in the Brazilian Amazon. We compiled species composition data for 34 Passeriformes assemblages, 12 in savannas and 22 in forests. We calculated the functional (Rao's quadratic entropy, FD Q ) and phylogenetic diversities (mean pairwise distance, MPD, and mean nearest taxon distance, MNTD), and the functional beta diversity to investigate the potential role of biogeographic history in shaping ecological traits and species lineages of both suborders. The functional diversity of Passeri was higher than for Tyranni in both habitats. The MPD for Tyranni was higher than for Passeri in forests; however, there was no difference between the suborders in savannas. In savannas, Passeri presented higher MNTD than Tyranni, while in forest areas, Tyranni assemblages showed higher MNTD than Passeri. We found a high functional turnover (~75%) between Passeri and Tyranni in both habitats. The high functional diversity of Passeri in both habitats is due to the high diversity of ecological traits exhibited by species of this group, which enables the exploitation of a wide variety of resources and foraging strategies. The higher Tyranni MPD and MNTD in forests is likely due to Tyranni being older settlers in this habitat, resulting in the emergence and persistence of more lineages. The higher Passeri MNTD in savannas can be explained by the existence of a larger number of different Passeri lineages adapted to this severe habitat. The high functional turnover between the suborders in both habitats suggests an ecological strategy to avoid niche overlap. We investigated the functional and phylogenetic diversity of Passeriformes (Passeri and Tyranni suborders) in Amazonian, and the functional beta diversity. The patterns of functional and phylogenetic diversity were a result of both the biogeographic history of each bird group, the occurrence within each habitat type, as well as the different ecological strategies shown by the species.
    Electronic ISSN: 2045-7758
    Topics: Biology
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  • 18
    Publication Date: 2018-03-07
    Description: The reproductive stages of the life cycle are crucial in explaining the distribution patterns of plant species because of their extreme vulnerability to environmental conditions. Despite reported evidence that seed germination is related to habitat macroclimatic characteristics, such as mean annual temperature, the effect of this trait in controlling plant species distribution has not yet been systematically and quantitatively evaluated. To learn whether seed germination can predict species distribution along altitude gradients, we examined germination data of 36 Rhododendron species in southeastern Tibet originating from contrasting altitudes, habitats, plant heights, seed masses, and phylogenies. Germination varied significantly with altitude, habitat, plant height, and phylogeny and was higher in the light than in the dark. Germination percentage was highest at 10:20°C in the light and 15:25°C in the dark. As altitude increased, germination percentages first rose and then decreased, being highest at 3,500–4,000 m. Germination percentage and rate were highest on rocky slopes, increasing as seed mass and plant height rose. Variations in germination percentage and rate were not significant at subgenera, section, and subsection levels, but they were significant at species level. The results suggested that the relationship between germination and altitude may provide insights into species distribution patterns. Further, germination patterns are a result of long-term evolution as well as taxonomic constraints. The reproductive stages of the life cycle are crucial in explaining the distribution patterns of plant species because of their extreme vulnerability to environmental conditions. Phylogeny, habitat together with biological and ecological factors can influence germination of 36 subalpine Rhododendron species from the eastern Tibetan Plateau.
    Electronic ISSN: 2045-7758
    Topics: Biology
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  • 19
    Publication Date: 2018-03-07
    Description: Mounting evidence has indicated that engaging in extrapair copulations (EPCs) might be maladaptive or detrimental to females. It is unclear why such nonadaptive female behavior evolves. In this study, we test two hypotheses about the evolution of female EPC behavior using population genetic models. First, we find that both male preference for allocating extra effort to seek EPCs and female pursuit behavior without costs can be maintained and remain polymorphic in a population via frequency-dependent selection. However, both behaviors cannot evolve when females with pursuit behavior suffer from a decline in male parental care. Second, we present another novel way in which female pursuit behavior can evolve; indirect selection can act on this behavior through a ratchet-like mechanism involving oscillating linkage disequilibria between the target EPC pursuit locus and two other loci determining male mate choice and a female sexual signal. Although the overall positive force of such indirect selection is relatively weak, our results suggest that it may still play a role in promoting the evolution of female EPC behavior when this behavior is nonadaptive (i.e., it is neutral) or only somewhat maladaptive (e.g., males only occasionally lower parental care when their mates pursue EPCs). Little is known about the evolution of nonadaptive female extrapair copulation (EPC) behavior. We find that such a behavior can be maintained and remain polymorphic in a population via frequency-dependent selection when there is no cost for females. Also, indirect selection can act on this behavior through a ratchet-like mechanism involving oscillating linkage disequilibria between the target EPC pursuit locus and two other loci determining male mate choice and a female sexual signal.
    Electronic ISSN: 2045-7758
    Topics: Biology
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  • 20
    Publication Date: 2018-03-07
    Description: In pediatric cancer, we advocate for trio sequencing of the child and its parents. This method can have substantial implications for cancer prevention in parents and siblings and even in more distant family members. It does not only help to identify a putative classical cancer predisposition syndrome in the index patient, but also detects the combinatorial effect of two independent risk variants in the same signaling pathway. This type of inheritance pattern could contribute to explaining the early occurrence of cancer in children and young adults and thereby inform early diagnosis, screening and preventive measures. From identifying a putative classical cancer predisposition syndrome in the index patient, trio-sequencing can also detect a potential combinatorial effect of two independent risk variants in the same signaling pathway. M. Kuhlen and A. Borkhardt explain here why they advocate for it.
    Print ISSN: 1757-4676
    Electronic ISSN: 1757-4684
    Topics: Medicine
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  • 21
    Publication Date: 2018-03-07
    Description: Ecotypic differentiation in the tussock-forming sedge Eriophorum vaginatum has led to the development of populations that are locally adapted to climate in Alaska's moist tussock tundra. As a foundation species, E. vaginatum plays a central role in providing topographic and microclimatic variation essential to these ecosystems, but a changing climate could diminish the importance of this species. As Arctic temperatures have increased, there is evidence of adaptational lag in E. vaginatum , as locally adapted ecotypes now exhibit reduced population growth rates. Whether there is a physiological underpinning to adaptational lag is unknown. Accordingly, this possibility was investigated in reciprocal transplant gardens. Tussocks of E. vaginatum from sites separated by ~1° latitude (Coldfoot: 67°15′N, Toolik Lake: 68°37′, Sagwon: 69°25′) were transplanted into the Toolik Lake and Sagwon sites and exposed to either an ambient or an experimental warming treatment. Five tussocks pertreatment combination were measured at each garden to determine photosynthetic capacity (i.e., V cmax and J max ) and dark respiration rate ( R d ) at measurement temperatures of 15, 20, and 25°C. Photosynthetic enhancements or homeostasis were observed for all ecotypes at both gardens under increased growth temperature, indicating no negative effect of elevated temperature on photosynthetic capacity. Further, no evidence of thermal acclimation in R d was observed for any ecotype, and there was little evidence of ecotypic variation in R d . As such, no physiological contribution to adaptational lag was observed given the increase in growth temperature (up to ~2°C) provided by this study. Despite neutral to positive effects of increased growth temperature on photosynthesis in E. vaginatum , it appears to confer no lasting advantage to the species. As Arctic temperatures have risen, the foundation species Eriophorum vaginatum has begun to exhibit adaptational lag. The physiological underpinning to this process was examined, and we found that increased growth temperature had neutral to positive effects on photosynthetic capacity and respiration. Over the range of growth temperatures examined in this study (up to 2°C), no negative physiological effects were observed.
    Electronic ISSN: 2045-7758
    Topics: Biology
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  • 22
    Publication Date: 2018-03-07
    Description: Trade-offs associated with sexual size dimorphism (SSD) are well documented across the Tree of Life. However, studies of SSD often do not consider potential investment trade-offs between metabolically expensive structures under sexual selection and other morphological modules. Based on the expectations of the expensive tissue hypothesis, investment in one metabolically expensive structure should come at the direct cost of investment in another. Here, we examine allometric trends in the ontogeny of oyster toadfish ( Opsanus tau ) to test whether investment in structures known to have been influenced by strong sexual selection conform to these expectations. Despite recovering clear changes in the ontogeny of a sexually selected trait between males and females, we find no evidence for predicted ontogenetic trade-offs with metabolically expensive organs. Our results are part of a growing body of work demonstrating that increased investment in one structure does not necessarily drive a wholesale loss of mass in one or more organs. Organisms are faced with a finite energy budget with which to accumulate biomass in developing tissues, raising the question of how sexual selection imposes trade-offs in organ investment. We test the expectations of the expensive tissue hypothesis (ETH) across the ontogeny of oyster toadfishes, a species in which males are under strong sexual selection for a metabolically expensive acoustic repertoire that involves maintaining the fastest twitching muscles of any vertebrates. However, despite finding clear evidence of sexual dimorphism, we failed to recover any evidence supporting the expectations of the ETH.
    Electronic ISSN: 2045-7758
    Topics: Biology
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  • 23
    Publication Date: 2018-03-07
    Description: Terrestrial primary production is a fundamental ecological process and a crucial component in understanding the flow of energy through trophic levels. The global MODIS gross primary production (GPP) and net primary production (NPP) products (MOD17) are widely used for monitoring GPP and NPP at coarse resolutions across broad spatial extents. The coarse input datasets and global biome-level parameters, however, are well-known limitations to the applicability of the MOD17 product at finer scales. We addressed these limitations and created two improved products for the conterminous United States (CONUS) that capture the spatiotemporal variability in terrestrial production. The MOD17 algorithm was utilized with medium resolution land cover classifications and improved meteorological data specific to CONUS in order to produce: (a) Landsat derived 16-day GPP and annual NPP at 30 m resolution from 1986 to 2016 (GPP L 30 and NPP L 30 , respectively); and (b) MODIS derived 8-day GPP and annual NPP at 250 m resolution from 2001 to 2016 (GPP M 250 and NPP M 250 respectively). Biome-specific input parameters were optimized based on eddy covariance flux tower-derived GPP data from the FLUXNET2015 database. We evaluated GPP L 30 and GPP M 250 products against the standard MODIS GPP product utilizing a select subset of representative flux tower sites, and found improvement across all land cover classes except croplands. We also found consistent interannual variability and trends across NPP L 30 , NPP M 250 , and the standard MODIS NPP product. We highlight the application potential of the production products, demonstrating their improved capacity for monitoring terrestrial production at higher levels of spatial detail across broad spatiotemporal scales. We produced two higher resolution primary production datasets, using better input data than currently existing datasets. These products more closely match the scale of many ecological processes and management activities, and will facilitate better understandings of production dynamics. Our products correspond well with other production datasets at multiple scales. The products fill a critical gap in our ability to monitor and assess terrestrial production dynamics in relation to many ecological processes and land use change. As production is a foundational ecological process and ecosystem service, understanding these dynamics is critical for environmental sustainability.
    Electronic ISSN: 2056-3485
    Topics: Architecture, Civil Engineering, Surveying , Biology
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  • 24
    Publication Date: 2018-03-09
    Print ISSN: 1015-6305
    Electronic ISSN: 1750-3639
    Topics: Medicine
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  • 25
    Publication Date: 2018-03-09
    Print ISSN: 1015-6305
    Electronic ISSN: 1750-3639
    Topics: Medicine
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  • 26
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    Wiley-Blackwell
    Publication Date: 2018-03-09
    Print ISSN: 1015-6305
    Electronic ISSN: 1750-3639
    Topics: Medicine
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  • 27
    Publication Date: 2018-03-09
    Description: ABSTRACT Down syndrome (DS) is a genetic condition associated with impairment in several cognitive domains. Previous evidence showed a notable neurogenesis reduction in the hippocampal region of DS fetuses, which may account for the impairment of declarative memory that characterizes DS starting from early life stages. The fusiform gyrus (FG) and the inferior temporal gyrus (ITG) play a key role in visual recognition memory, a function that is impaired in children and adults with DS. The goal of the current study was to establish whether fetuses with DS (17-21 weeks of gestation) exhibit neuroanatomical alterations in the FG and ITG that may underlie recognition memory impairment. We found that the FG and ITG of fetuses with DS had a reduced thickness and fewer cells in comparison with euploid fetuses. Moreover, DS fetuses had fewer cells expressing the neuronal marker NeuN than euploid fetuses, but a similar number of cells expressing the astrocytic marker GFAP and, consequently, a higher percentage of astrocytes. Immunohistochemistry for calretinin (CR), a marker of GABAergic interneurons, showed that in DS fetuses the ratio of CR-positive versus CR-negative cells was greater than in euploid fetuses, both in the FG (+77%) and ITG (+61%). An increased ratio of CR-positive versus CR-negative cells was also found in the entorhinal cortex, hippocampus and dentate gyrus. Results provide novel evidence that the FG and ITG of DS fetuses exhibit numerous developmental defects. These defects may underlie the functional alterations in visual recognition memory observed in children with DS. This article is protected by copyright. All rights reserved.
    Print ISSN: 1015-6305
    Electronic ISSN: 1750-3639
    Topics: Medicine
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  • 28
    Publication Date: 2018-03-09
    Description: In this report, we describe the circularly polarized luminescence (CPL) of the RNA duplexes having one to four 2′-O-pyrene modified uridines ( Upy ) and the DNA duplexes having two, four, and six pyrene modified non-nucleosidic linkers ( Py ). Both the pyrene π-stack arrays formed on the RNA and DNA double helical structures exhibited pyrene excimer fluorescence. In the pyrene-modified RNA systems, the RNA duplex having four Upy s gives CPL emission with g lum value of 〈0.01 at 480 nm. The structure of pyrene stacks on the RNA duplex may be rigidly regulated with increase in the Upy domains, which resulted in the CPL emission. In the DNA systems, the pyrene-modified duplexes containing two and four Pys exhibited CPL emission with g lum values of 〈0.001 at 505 nm. The pyrene π-stack arrays presented here show CPL emission. However, the g lum values are relatively small when compared with our previous system consisting of the pyrene-zipper arrays on RNA.
    Print ISSN: 0899-0042
    Electronic ISSN: 1520-636X
    Topics: Chemistry and Pharmacology
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  • 29
    Publication Date: 2018-03-09
    Description: The management of conflicts between wildlife conservation and agricultural practices often involves the implementation of strategies aimed at reducing the cost of wildlife impacts on crops. Vital to the success of these strategies is the perception that changes in management efforts are synchronised relative to changes in impact levels, yet this expectation is never evaluated. We assess the level of synchrony between time series of population counts and management effort in the context of conflicts between agriculture and five populations of large grazing birds in northern Europe. We reveal inconsistent patterns of synchrony and asynchrony between changes in population counts and impact management effort relating to population harvesting, monetary payments or scaring practices. This variation is likely due to differing management aims, the existence of lags between management decisions and population monitoring, and the inconsistent use of predictive models across case studies. Overall, our findings highlight the need for more adaptive and timely responses of management to changes in target species numbers so as not to unexpectedly increase social conflicts and jeopardise the status of wildlife populations. This article is protected by copyright. All rights reserved
    Print ISSN: 1755-263X
    Electronic ISSN: 1755-263X
    Topics: Biology
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  • 30
    Publication Date: 2018-03-09
    Description: Alarm signals released after predator attack function as reliable public information revealing areas of high risk. The utility of this information can extend beyond species boundaries, benefiting heterospecifics capable of recognizing and responding appropriately to the signal. Nonmutually exclusive hypotheses explaining the acquisition of heterospecific reactivity to cues suggest it could be conserved phylogenetically following its evolution in a common ancestor (a species-level effect) and/or learned during periods of shared risk (a population-level effect; e.g., shared predators). Using a laboratory-based space-use behavioral assay, we tested the response of sea lamprey ( Petromyzon marinus ) to the damage-released alarm cues of five confamilial (sympatric and allopatric) species and two distantly related out-groups: a sympatric teleost (white sucker Catostomus commersonii ) and an allopatric agnathan (Atlantic hagfish Myxine glutinosa ). We found that sea lamprey differed in their response to conspecific and heterospecific odors; exhibiting progressively weaker avoidance of cues derived from more phylogenetically distant confamilials regardless of current overlap in distribution. Odors from out-groups elicited no response. These findings suggest that a damage-released alarm cue is at least partially conserved within the Petromyzontidae and that sea lamprey perceives predator attacks directed to closely related taxa. These findings are consistent with similar observations from gastropod, amphibian and bony fish taxa, and we discuss this in an eco-evo context to provide a plausible explanation for the acquisition and maintenance of the response in sea lamprey. Alarm signals released after predator attack function as reliable public information revealing areas of high risk. Using a laboratory-based space-use behavioral assay, we tested the response of sea lamprey ( Petromyzon marinus ) to the damage-released alarm cues of five confamilial (sympatric and allopatric) species and two distantly related out-groups: a sympatric teleost and a marine agnathan. We found that sea lamprey exhibited progressively weaker avoidance of cues derived from more phylogenetically distant confamilials regardless of current overlap in distribution, whereas odors from out-groups elicited no response.
    Electronic ISSN: 2045-7758
    Topics: Biology
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  • 31
    Publication Date: 2018-03-09
    Description: Genomic studies have been used to identify genes underlying many important plant secondary metabolic pathways. However, genes for salicinoid phenolic glycosides (SPGs)—ecologically important compounds with significant commercial, cultural, and medicinal applications—remain largely undescribed. We used a linkage map derived from a full-sib population of hybrid cottonwoods ( Populus spp.) to search for quantitative trait loci (QTL) for the SPGs salicortin and HCH-salicortin. SSR markers and primer sequences were used to anchor the map to the V3.0 P. trichocarpa genome. We discovered 21 QTL for the two traits, including a major QTL for HCH-salicortin ( R 2  = .52) that colocated with a QTL for salicortin on chr12. Using the V3.0 Populus genome sequence, we identified 2,983 annotated genes and 1,480 genes of unknown function within our QTL intervals. We note ten candidate genes of interest, including a BAHD-type acyltransferase that has been potentially linked to Populus SPGs. Our results complement other recent studies in Populus with implications for gene discovery and the evolution of defensive chemistry in a model genus. To our knowledge, this is the first study to use a full-sib mapping population to identify QTL intervals and gene lists associated with SPGs. Salicinoid phenolic glycosides (SPGs) are important secondary metabolites with numerous ecological, commercial, and ethnobotanical applications. However, the pathways controlling the expression of SPGs remain conspicuously underscribed. Here, discuss 25 quantitative trait loci (QTL) associated with the salicinoid phenolic gylcosides, salicortin and HCH-salicortin, and a number of potential candidate genes that occur within our QTL intervals.
    Electronic ISSN: 2045-7758
    Topics: Biology
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  • 32
    Publication Date: 2018-03-09
    Description: Knowledge of aquatic food resources entering terrestrial systems is important for food web studies and conservation planning. Bats, among other terrestrial consumers, often profit from aquatic insect emergence and their activity might be closely related to such events. However, there is a lack of studies which monitor bat activity simultaneously with aquatic insect emergence, especially from lakes. Thus, our aim was to understand the relationship between insect emergence and bat activity, and investigate whether there is a general spatial or seasonal pattern at lakeshores. We assessed whole-night bat activity using acoustic monitoring and caught emerging and aerial flying insects at three different lakes through three seasons. We predicted that insect availability and seasonality explain the variation in bat activity, independent of the lake size and characteristics. Spatial (between lakes) differences of bat activity were stronger than temporal (seasonal) differences. Bat activity did not always correlate to insect emergence, probably because other factors, such as habitat characteristics, or bats’ energy requirements, play an important role as well. Aerial flying insects explained bat activity better than the emerged aquatic insects in the lake with lowest insect emergence. Bats were active throughout the night with some activity peaks, and the pattern of their activity also differed among lakes and seasons. Lakes are important habitats for bats, as they support diverse bat communities and activity throughout the night and the year when bats are active. Our study highlights that there are spatial and temporal differences in bat activity and its hourly nocturnal pattern, that should be considered when investigating aquatic–terrestrial interactions or designing conservation and monitoring plans. We assessed bat activity (using acoustic monitoring) at the shores of three lakes and collected emerged aquatic insects and aerial flying insects. Bat activity showed seasonal fluctuations, but it did not necessarily follow insect emergence. Lakes, regardless of their size or their characteristics, are important habitats for bats, as they support diverse bat communities and activity throughout the night and the year when bats are active.
    Electronic ISSN: 2045-7758
    Topics: Biology
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  • 33
    Publication Date: 2018-03-09
    Description: Unexpected fetal loss is one of the common complications of pregnancy; however, the pathogenesis of many miscarriages, particularly those not associated with infections, is unknown. We previously found that activated DEC-205 + dendritic cells (DCs) and NK1.1 + invariant natural killer T (iNKT) cells are recruited into the myometrium of mice when miscarriage is induced by the intraperitoneal administration of α-galactosylceramide (α-GalCer). Here we demonstrate that the adoptive transfer of DEC-205 + bone marrow-derived DCs cocultured with α-GalCer (DEC-205 + BMDCs-c/w-α-GalCer) directly induced marked fetal loss by syngeneic pregnant C57BL/6 (B6) mice and allogeneic mice (B6 (♀) × BALB/c (♂)), which was accompanied by the accumulation of activated iNKT cells in the myometrium. Further, the adoptive transfer of NK1.1 + iNKT cells obtained from B6 mice injected with α-GalCer facilitated miscarriages in syngeneic Jα18(-/-) (iNKT cell-deficient) mice. These results suggest that DEC-205 + DCs and NK1.1 + iNKT cells play crucial roles required for the initiation of fetal loss associated with stimulation by glycolipid antigens and sterile inflammation. This article is protected by copyright. All rights reserved
    Print ISSN: 0014-2980
    Electronic ISSN: 1521-4141
    Topics: Medicine
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  • 34
    Publication Date: 2018-03-09
    Description: High salt consumption has since long been associated with elevated blood pressure and cardiovascular disease. Recently, mouse studies suggested that a high dietary salt intake exacerbates the clinical manifestations of autoimmunity. Using naïve cells ex vivo after pre-exposure of mice to high salt intake, we show that increased salt exposure affects the viability and effector functions of immune cells. CD4 + T cells evidenced a pro-inflammatory phenotype characterized by increased secretion of IFN γ and IL-17A, when exposed to high salt concentrations in vitro . Interestingly, this phenotype was associated with osmotic pressure, since replacing salt for D-mannitol resulted in similar observations. However, high salt intake did not alter the development of T cell-dependent autoimmunity. Instead, recruitment of peritoneal macrophages was increased in mice pre-exposed to high salt concentrations. These cells had an increased production of both TNF α and IL-10, suggesting that salt stimulates expansion/differentiation of different subsets of macrophages. Moreover, mice pre-exposed to high salt intake developed exacerbated symptoms of colitis, when induced by dextran sulfate sodium. The aggravated colitis in salt exposed animals was associated with a higher frequency of CD4 + T cells and CD11b + CD64 + macrophages producing TNF α . These phenotypes correlated with elevated titers of fecal IgA and higher lymphocytic cellularity in the colon, mesenteric lymph nodes and spleen. In conclusion, we report here that high salt intake affects both lymphoid and myeloid cells ex vivo . However, the effects of high salt intake in vivo seem less pronounced in terms of CD4 + T cell responses, whereas macrophage-dependent pathologies are significantly influenced. This article is protected by copyright. All rights reserved.
    Print ISSN: 0019-2805
    Electronic ISSN: 1365-2567
    Topics: Medicine
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  • 35
    Publication Date: 2018-03-09
    Description: Neurodegenerative diseases, the leading cause of morbidity and disability is gaining increased attention as it imposes a considerable socioeconomic impact, due in part to the ageing community. Neuronal damage is a pathological hallmark of Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, spinocerebellar ataxia and multiple sclerosis, although such damage is also observed following neurotropic viral infections, stroke, genetic white matter diseases and paraneoplastic disorders. Despite the different aetiologies e.g. infections, genetic mutations, trauma and protein aggregations, neuronal damage is frequently associated with chronic activation of an innate immune response in the CNS. The growing awareness that the immune system is inextricably involved in shaping the brain during development as well as mediating damage but also regeneration and repair, has stimulated therapeutic approaches to modulate the immune system in neurodegenerative diseases. Here, we review the current understanding of how astrocytes and microglia, as well as neurons and oligodendrocytes, shape the neuroimmune response during development, and how aberrant responses that arise due to genetic or environmental triggers may predispose the CNS to neurodegenerative diseases. We discuss the known interactions between the peripheral immune system and the brain, and review the current concepts on how immune cells enter and leave the CNS. A better understanding of neuroimmune interactions during development and disease will be key to further manipulating these responses and the development of effective therapies to improve quality of life, and reduce the impact of neuroinflammatory and degenerative diseases. This article is protected by copyright. All rights reserved.
    Print ISSN: 0019-2805
    Electronic ISSN: 1365-2567
    Topics: Medicine
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  • 36
    Publication Date: 2018-03-09
    Description: Background Identification of patients with progressive chronic kidney disease (CKD) and those likely to respond to candidate therapeutics is urgently needed. Functional MRI measurements have shown promise. However, knowledge about the consistency of the measurements is essential to conduct longitudinal studies. Purpose/Hypothesis To investigate the consistency of repeated functional MRI measurements in healthy subjects. Study Type Prospective, longitudinal study. Subjects Seventeen healthy subjects were examined on two different occasions, 18 months apart. Field Strength/Sequence Multiple gradient-recalled-echo, 2D navigator-gated flow-sensitive alternating inversion recovery True-FISP and spin-echo planar diffusion-weighted sequences were used on a 3T scanner. Images were acquired on two different scanner configurations. Assessment Blood oxygenation level-dependent (BOLD) R2*, arterial spin labeling (ASL) perfusion-derived blood flow (BF) and apparent diffusion coefficient (ADC) maps were analyzed using a custom image processing toolbox. Regions of interest (ROIs) were placed on renal cortex, medulla, and whole kidney. Multiple researchers were involved in defining the ROIs. Statistical Tests Intra- and intersubject coefficients of variation (CV) and Bland–Altman plots were used to measure consistency and evaluate bias in the measurements. A nonparametric Wilcoxon test was used to compare differences between two timepoints. Results The intrasubject CV for R2* and ADC were 6.8% and 5.3% with small (−3.8 and 5.3%) bias, respectively, comparing baseline and 18-month data. Intrasubject CV for renal cortex BF was higher (18.7%) compared to R2* and ADC, but comparable to prior literature values over shorter durations. It also exhibited a larger bias (−15.4%) between two timepoints and significantly lower values ( P  = 0.022) at 18-month data. Data Conclusion All three MRI parameters over 18 months, even with a scanner upgrade and involving multiple observers, showed good consistency. These results are useful for the interpretation of longitudinal data and support the use of these methods to monitor progression in patients with CKD. Level of Evidence : 1 Technical Efficacy : Stage 1 J. Magn. Reson. Imaging 2018.
    Print ISSN: 1053-1807
    Electronic ISSN: 1522-2586
    Topics: Medicine
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  • 37
    Publication Date: 2018-03-09
    Description: Background Subject motion in positron emission tomography (PET) studies leads to image blurring and artifacts; simultaneously acquired magnetic resonance imaging (MRI) data provides a means for motion correction (MC) in integrated PET/MRI scanners. Purpose To assess the effect of realistic head motion and MR-based MC on static [ 18 F]-fluorodeoxyglucose (FDG) PET images in dementia patients. Study Type Observational study. Population Thirty dementia subjects were recruited. Field Strength/Sequence 3T hybrid PET/MR scanner where EPI-based and T 1 -weighted sequences were acquired simultaneously with the PET data. Assessment Head motion parameters estimated from high temporal resolution MR volumes were used for PET MC. The MR-based MC method was compared to PET frame-based MC methods in which motion parameters were estimated by coregistering 5-minute frames before and after accounting for the attenuation-emission mismatch. The relative changes in standardized uptake value ratios (SUVRs) between the PET volumes processed with the various MC methods, without MC, and the PET volumes with simulated motion were compared in relevant brain regions. Statistical Tests The absolute value of the regional SUVR relative change was assessed with pairwise paired t -tests testing at the P  = 0.05 level, comparing the values obtained through different MR-based MC processing methods as well as across different motion groups. The intraregion voxelwise variability of regional SUVRs obtained through different MR-based MC processing methods was also assessed with pairwise paired t -tests testing at the P  = 0.05 level. Results MC had a greater impact on PET data quantification in subjects with larger amplitude motion (higher than 18% in the medial orbitofrontal cortex) and greater changes were generally observed for the MR-based MC method compared to the frame-based methods. Furthermore, a mean relative change of ∼4% was observed after MC even at the group level, suggesting the importance of routinely applying this correction. The intraregion voxelwise variability of regional SUVRs was also decreased using MR-based MC. All comparisons were significant at the P  = 0.05 level. Data Conclusion Incorporating temporally correlated MR data to account for intraframe motion has a positive impact on the FDG PET image quality and data quantification in dementia patients. Level of Evidence: 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018.
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    Electronic ISSN: 1522-2586
    Topics: Medicine
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  • 38
    Publication Date: 2018-03-09
    Description: Background Lung T 1 is a potential translational biomarker of lung disease. The precision and repeatability of variable flip angle (VFA) T 1 mapping using modern 3D ultrashort echo time (UTE) imaging of the whole lung needs to be established before it can be used to assess response to disease and therapy. Purpose To evaluate the feasibility of regional lung T 1 quantification with VFA 3D-UTE and to investigate long- and short-term T 1 repeatability in the lungs of naive mice. Study type Prospective preclinical animal study. Population Eight naive mice and phantoms. Field strength/Sequence 3D free-breathing radial UTE (8 μs) at 4.7T. Assessment VFA 3D-UTE T 1 calculations were validated against T 1 values measured with inversion recovery (IR) in phantoms. Lung T 1 and proton density ( S 0 ) measurements of whole lung and muscle were repeated five times over 1 month in free-breathing naive mice. Two consecutive T 1 measurements were performed during one of the imaging sessions. Statistical Tests Agreement in T 1 between VFA 3D-UTE and IR in phantoms was assessed using Bland–Altman and Pearson 's correlation analysis. The T 1 repeatability in mice was evaluated using coefficient of variation (CV), repeated-measures analysis of variance (ANOVA), and paired t -test. Results Good T 1 agreement between the VFA 3D-UTE and IR methods was found in phantoms. T 1 in lung and muscle showed a 5% and 3% CV (1255 ± 63 msec and 1432 ± 42 msec, respectively, mean ± SD) with no changes in T 1 or S 0 over a month. Consecutive measurements resulted in an increase of 2% in both lung T 1 and S 0 . Data Conclusion VFA 3D-UTE shows promise as a reliable T 1 mapping method that enables full lung coverage, high signal-to-noise ratio (∼25), and spatial resolution (300 μm) in freely breathing animals. The precision of the VFA 3D-UTE method will enable better design and powering of studies. Level of Evidence: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018.
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    Electronic ISSN: 1522-2586
    Topics: Medicine
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  • 39
    Publication Date: 2018-03-09
    Description: BACKGROUND The coexistence of hepatic iron and fat is common in patients with hyperferritinemia, which plays an interactive and aggressive role in the progression of diseases (fibrosis, cirrhosis, and hepatocellular carcinomas). PURPOSE To evaluate a modified high-speed T 2 -corrected multi-echo, single voxel spectroscopy sequence (HISTOV) for liver iron concentration (LIC) quantification in patients with hyperferritinemia, with simultaneous fat fraction (FF) estimation. STUDY TYPE Retrospective cohort study. POPULATION Thirty-eight patients with hyperferritinemia were enrolled. FIELD STRENGTH/SEQUENCE HISTOV, a fat-saturated multi-echo gradient echo (GRE) sequence, and a spin echo sequence (FerriScan) were performed at 1.5T. ASSESSMENT R 2 of the water signal and FF were calculated with HISTOV, and values were derived from the GRE sequence, with R 2 and LIC from FerriScan serving as the references. STATISTICAL TESTS Linear regression, correlation analyses, receiver operating characteristic analyses, and Bland-Altman analyses were conducted. RESULTS Abnormal hepatic iron load was detected in 32/38 patients, of whom 10/32 had coexisting steatosis. Strong correlation was found between and FerriScan-LIC ( R 2 = 0.861), and between HISTOV-R 2_ water and FerriScan-R 2 ( R 2  = 0.889). Furthermore, HISTOV-R 2_ water was not correlated with HISTOV-FF. The area under the curve (AUC) for HISTOV-R 2_ water was 0.974, 0.971, and 1, corresponding to clinical FerriScan-LIC thresholds of 1.8, 3.2, and 7.0 mg/g dw, respectively. No significant difference in the AUC was found between HISTOV-R 2_ water and at any of the LIC thresholds, with P -values of 0.42, 0.37, and 1, respectively. HISTOV-LIC showed excellent agreement with FerriScan-LIC, with a mean bias of 0.00 ± 1.18 mg/g dw, whereas the mean bias between GRE-LIC and FerriScan-LIC was 0.53 ± 1.49 mg/g dw. DATA CONCLUSION HISTOV is useful for the quantification and grading of liver iron overload in patients with hyperferritinemia, particularly in cases with coexisting steatosis. HISTOV-LIC showed no systematic bias compared with FerriScan-LIC, making it a promising alternative for iron quantification. Level of Evidence : 3 Technical Efficacy Stage 2 J. Magn. Reson. Imaging 2018.
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  • 40
    Publication Date: 2018-03-09
    Description: Background Renal steatosis (fatty kidney) is a potential biomarker for obesity-related renal disease; however, noninvasive assessment of renal fat content remains a technical challenge. Purpose To evaluate reproducibility and explore clinical application of renal metabolic imaging for the quantification of renal triglyceride content (TG) using proton magnetic resonance spectroscopy ( 1 H-MRS). Study type Reproducibility and clinical cohort study. Population Twenty-three healthy volunteers (mean age 30.1 ± 13.4 years) and 15 patients with type 2 diabetes mellitus (T2DM) (mean age 59.3 ± 7.0 years). Field Strength/Sequence 3T, single-voxel point resolved spectroscopy (PRESS). Assessment Intra- and interexamination reproducibility of renal TG was assessed in healthy volunteers, and compared to T2DM patients. Intraexamination differences were obtained by repeating the 1 H-MRS measurement directly after the first 1 H-MRS without repositioning of the subject or changing surface coil and measurement volumes. Interexamination variability was studied by repeating the scan protocol after removal and replacement of the subject in the magnet, and subsequent repositioning of body coil and measurement volumes. Statistical Tests Reproducibility was determined using Pearson's correlation and Bland–Altman analyses. Differences in TG% between healthy volunteers and T2DM patients were assessed using the Mann–Whitney U -test. Results After logarithmic (log) transformation, both intraexamination ( r  = 0.91, n  = 19) and interexamination ( r  = 0.73, n  = 9) measurements of renal TG content were highly correlated with the first renal TG measurements. Intraexamination and interexamination limits of agreement of renal log TG% were respectively [−1.36%, + 0.84%] and [−0.77%, + 0.62%]. Backtransformed limits of agreement were [−0.89%,+0.57%] and [−0.55%, + 0.43%] multiplied by mean TG for intra- and interexamination measurements. Overall median renal TG content was 0.12% [0.08, 0.22; 25th percentile, 75th percentile] in healthy volunteers and 0.20% [0.13, 0.22] in T2DM patients ( P  = 0.08). Data Conclusion Renal metabolic imaging using 3T 1 H-MRS is a reproducible technique for the assessment of renal triglyceride content. Level of Evidence : 3 Technical Efficacy : Stage 1 J. Magn. Reson. Imaging 2018.
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  • 41
    Publication Date: 2018-03-09
    Description: Background The incremental value of dynamic contrast-enhanced (DCE) imaging in localizing radiorecurrent prostate cancer is uncertain. Purpose To assess the added-value of DCE imaging to the combination T 2 -weighted imaging (T 2 W)+diffusion-weighted imaging (DWI) in detecting locally radiorecurrent prostate cancer (PCa), by radiologists with different levels of experience. Study Type Analytic retrospective study. Population In all, 52 men with biological suspected PCa recurrence after radiotherapy were retrospectively included. Field Strength/Sequence All men underwent prostatic MRI (1.5T or 3T), including T 2 W, DWI, and DCE imagings, before biopsies. Assessment Two junior (6 months' experience) and two senior readers (more than 3 years' experience) independently assigned a Likert score for each prostatic sextant on T 2 W+DW+DCE imagings, then on T 2 W+DW imagings, 4 weeks later. Statistical Tests The reference standard was prostatic biopsies. For two levels of positivity of Likert score, 3/5 and 4/5, sensitivity, specificity, area under the receiver operating curve (AUC), and interreader agreement were compared. Results T 2 W+DWI+DCE and T 2 W+DWI imaging had similar AUC at lobe and sextant level (0.853–0.946 vs. 0.819–0.955, P from 0.071–0.534). Using a Likert score ≥4/5, T 2 W+DWI+DCE significantly improved the sensitivity for junior readers at the patient, lobe, and sextant level (40–80% vs. 22–66%, P  〈 0.0001–0.041). Sensitivity was not significantly modified with DCE imaging for senior readers (54–95% vs. 50–91%, P from 0.074–1). Specificity was not modified for all readers (50–100% vs. 50%–100%, P from 0.134–1). DCE imaging improved interreader agreement for a Likert score ≥4/5 (kappa from 0.6–0.73 vs. 0.38–0.73). Data Conclusion The addition of DCE imaging did not significantly improve accuracy in recurrent PCa detection after radiotherapy, whatever the level of experience of the readers. However, the addition of DCE imaging slightly improved the sensitivity for less-experienced readers and increased their diagnostic confidence. Level of Evidence : 3 Technical Efficacy : Stage 2 J. Magn. Reson. Imaging 2018.
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  • 42
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    Publication Date: 2018-03-09
    Print ISSN: 0899-1987
    Electronic ISSN: 1098-2744
    Topics: Medicine
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  • 43
    Publication Date: 2018-03-09
    Description: Triptolide is an active component from a Chinese herb, Tripterygium wilfordii which has been applied for treating immune-related diseases over centuries. Recently, it was reported that a variety of cancer cell lines could be sensitized to DNA-damage based chemotherapy drugs in combination with Triptolide treatment. In the present study, we show that a short time exposure (3 hours) to Triptolide,which did not trigger apoptosis, could specifically increase breast cancer cells sensitivity to Doxorubicin rather than other chemotherapy drugs including Paclitaxel, Fluorouracil, and Mitomycin .C. Further studies revealed Triptolide downregulated ATM expression and inhibited DNA damage response to DNA double- strand breaks. Moreover, the chemosensitization effect to Doxorubicin from Triptolide was attenuated by overexpression of ATM in breast cancer cells. Our findings suggest that Triptolide specifically chemosensitizes breast cancer cells to Doxorubicin prior to apoptosis initiation through downregulating ATM expression and inhibiting DNA damage response. This article is protected by copyright. All rights reserved
    Print ISSN: 0899-1987
    Electronic ISSN: 1098-2744
    Topics: Medicine
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  • 44
    Publication Date: 2018-03-09
    Description: ABSTRACT Growth factors, such as the transforming growth factor beta (TGFβ), play an important role in promoting metastasis of prostate cancer, thus understanding how TGFβ could induce prostate cancer cell migration may enable us to develop targeted strategies for advanced metastatic prostate cancer. To more clearly define the mechanism(s) involved in prostate cancer cell migration, we undertook a series of studies utilizing non-malignant prostate epithelial cells RWPE1 and prostate cancer DU145 and PC3 cells. Our studies show that increased cell migration was observed in prostate cancer cells, which was mediated through epithelial-to-mesenchymal transition (EMT). Importantly, addition of Mg 2+ , but not Ca 2+ , increased cell migration. Furthermore, TRPM7 expression which function as an Mg 2+ influx channel, was also increased in prostate cancer cells. Inhibition of TRPM7 currents by 2-APB, significantly blocked cell migration in both DU145 and PC3 cells. Addition of growth factor TGFβ showed a further increase in cell migration, which was again blocked by the addition of 2-APB. Importantly, TGFβ addition also significantly increased TRPM7 expression and function, and silencing of TRPM7 negated TGFβ-induced cell migration along with a decrease in EMT markers that shows loss of cell adhesion. Furthermore, resveratrol, which decreases prostate cancer cell migration, inhibited TRPM7 expression and function including TGFβ-induced cell migration and activation of TRPM7 function. Together, these results suggest that Mg 2+ influx via TRPM7 promotes cell migration by inducing EMT in prostate cancer cells and resveratrol negatively modulates TRPM7 function thereby inhibiting prostate cancer metastasis. This article is protected by copyright. All rights reserved
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  • 45
    Publication Date: 2018-03-09
    Description: Background There are few tissue-based biomarkers that can accurately predict prostate cancer (PCa) progression and aggressiveness. We sought to evaluate the clinical utility of prostate and breast overexpressed 1 (PBOV1) as a potential PCa biomarker. Methods Patient tumor samples were designated by Grade Groups using the 2014 Gleason grading system. Primary radical prostatectomy tumors were obtained from 48 patients and evaluated for PBOV1 levels using Western blot analysis in matched cancer and benign cancer-adjacent regions. Immunohistochemical evaluation of PBOV1 was subsequently performed in 80 cancer and 80 benign cancer-adjacent patient samples across two tissue microarrays (TMAs) to verify protein levels in epithelial tissue and to assess correlation between PBOV1 proteins and nuclear architectural changes in PCa cells. Digital histomorphometric analysis was used to track 22 parameters that characterized nuclear changes in PBOV1-stained cells. Using a training and test set for validation, multivariate logistic regression (MLR) models were used to identify significant nuclear parameters that distinguish Grade Group 3 and above PCa from Grade Group 1 and 2 PCa regions. Results PBOV1 protein levels were increased in tumors from Grade Group 3 and above (GS 4 + 3 and ≥ 8) regions versus Grade Groups 1 and 2 (GS 3 + 3 and 3 + 4) regions ( P  = 0.005) as assessed by densitometry of immunoblots. Additionally, by immunoblotting, PBOV1 protein levels differed significantly between Grade Group 2 (GS 3 + 4) and Grade Group 3 (GS 4 + 3) PCa samples ( P  = 0.028). In the immunohistochemical analysis, measures of PBOV1 staining intensity strongly correlated with nuclear alterations in cancer cells. An MLR model retaining eight parameters describing PBOV1 staining intensity and nuclear architecture discriminated Grade Group 3 and above PCa from Grade Group 1 and 2 PCa and benign cancer-adjacent regions with a ROC-AUC of 0.90 and 0.80, respectively, in training and test sets. Conclusions Our study demonstrates that the PBOV1 protein could be used to discriminate Grade Group 3 and above PCa. Additionally, the PBOV1 protein could be involved in modulating changes to the nuclear architecture of PCa cells. Confirmatory studies are warranted in an independent population for further validation.
    Print ISSN: 0270-4137
    Electronic ISSN: 1097-0045
    Topics: Medicine
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  • 46
    Publication Date: 2018-03-09
    Description: Background Undetectable End of Radiation PSA (EOR-PSA) has been shown to predict improved survival in prostate cancer (PCa). While validating the unfavorable intermediate-risk (UIR) and favorable intermediate-risk (FIR) stratifications among Johns Hopkins PCa patients treated with radiotherapy, we examined whether EOR-PSA could further risk stratify UIR men for survival. Methods A total of 302 IR patients were identified in the Johns Hopkins PCa database (178 UIR, 124 FIR). Kaplan-Meier curves and multivariable analysis was performed via Cox regression for biochemical recurrence free survival (bRFS), distant metastasis free survival (DMFS), and overall survival (OS), while a competing risks model was used for PCa specific survival (PCSS). Among the 235 patients with known EOR-PSA values, we then stratified by EOR-PSA and performed the aforementioned analysis. Results The median follow-up time was 11.5 years (138 months). UIR was predictive of worse DMFS and PCSS ( P  = 0.008 and P  = 0.023) on multivariable analysis (MVA). Increased radiation dose was significant for improved DMFS ( P  = 0.016) on MVA. EOR-PSA was excluded from the models because it did not trend towards significance as a continuous or binary variable due to interaction with UIR, and we were unable to converge a multivariable model with a variable to control for this interaction. However, when stratifying by detectable versus undetectable EOR-PSA, UIR had worse DMFS and PCSS among detectable EOR-PSA patients, but not undetectable patients. UIR was significant on MVA among detectable EOR-PSA patients for DMFS ( P  = 0.021) and PCSS ( P  = 0.033), while RT dose also predicted PCSS ( P  = 0.013). Conclusions EOR-PSA can assist in predicting DMFS and PCSS among UIR patients, suggesting a clinically meaningful time point for considering intensification of treatment in clinical trials of intermediate-risk men.
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    Electronic ISSN: 1097-0045
    Topics: Medicine
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  • 47
    Publication Date: 2018-03-09
    Description: Background Germline mutations in CHEK2 have been associated with prostate cancer (PCa) risk. Our objective is to examine whether germline pathogenic CHEK2 mutations can differentiate risk of lethal from indolent PCa. Methods A case-case study of 703 lethal PCa patients and 1455 patients with low-risk localized PCa of European, African, and Chinese origin was performed. Germline DNA samples from these patients were sequenced for CHEK2 . Mutation carrier rates and their association with lethal PCa were analyzed using the Fisher exact test and Kaplan-Meier survival analysis. Results In the entire study population, 40 (1.85%) patients were identified as carrying one of 15 different germline CHEK2 pathogenic or likely pathogenic mutations. CHEK2 mutations were detected in 16 (2.28%) of 703 lethal PCa patients compared with 24 (1.65%) of 1455 low-risk PCa patients ( P  = 0.31). No association was found between CHEK2 mutation status and early-diagnosis or PCa-specific survival time. However, the most common mutation in CHEK2 , c.1100delC (p.T367 fs), had a significantly higher carrier rate (1.28%) in lethal PCa patients than low-risk PCa patients of European American origin (0.16%), P  = 0.0038. The estimated Odds Ratio of this mutation for lethal PCa was 7.86. The carrier rate in lethal PCa was also significantly higher than that (0.46%) in 32 461 non-Finnish European subjects from the Exome Aggregation Consortium (ExAC) ( P  = 0.01). Conclusions While overall CHEK2 mutations were not significantly more common in men with lethal compared to low-risk PCa, the specific CHEK2 mutation, c.1100delC, appears to contribute to an increased risk of lethal PCa in European American men.
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  • 48
    Publication Date: 2018-03-09
    Description: Introduction The development of radioresistance in prostate cancer (PCa) is an important clinical issue and is still largely uninformed by personalized molecular characteristics. The aim of this study was to establish a platform that describes the early oncoproteomic response of human prostate tissue to radiation therapy (RT) using a prospective human tissue cohort. Methods Fresh and fixed transperineal biopsies from eight men with clinically localized tumors were taken prior to and 14 days following a single fraction of high-dose-rate brachytherapy. Quantitative protein analysis was achieved using an optimized protein extraction pipeline and subsequent data-independent acquisition mass spectroscopy (DIA-MS). Ontology analyses were used to identify enriched functional pathways, with the candidates further interrogated in formalin-fixed paraffin-embedded tissue biopsies from five additional patients. Results We obtained a mean coverage of 5660 proteins from fresh tissue biopsies; with the principal post-radiation change observed being an increase in levels amongst a total of 49 proteins exhibiting abundance changes. Many of these changes in abundance varied between patients and, typically to prostate cancer tissue, exhibited a high level of heterogeneity. Ontological analysis revealed the enrichment of the protein activation cascades of three immunological pathways: humoral immune response, leukocyte mediated immunity and complement activation. These were predominantly associated with the extracellular space. We validated significant expression differences in between 20% and 61% of these candidates using the separate fixed-tissue cohort and established their feasibility as an experimental tissue resource by acquiring quantitative data for a mean of 5152 proteins per patient. Discussion In this prospective study, we have established a sensitive and reliable oncoproteomic pipeline for the analysis of both fresh and formalin-fixed human PCa tissue. We identified multiple pathways known to be radiation-responsive and have established a powerful database of candidates and pathways with no current association with RT. This information may be beneficial in the advancement of personalized therapies and potentially, predictive biomarkers.
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  • 49
    Publication Date: 2018-03-09
    Description: Mass spectrometry (MS)-based immunopeptidomics has developed as one of the leading methodologies for comprehensive characterization of in vivo presented Human Leukocyte Antigen (HLA)-bound peptides. Unveiling the identity of HLA-bound peptides derived from diseased cells is crucial to gain knowledge on the constitution of efficient disease-specific T cell responses. The HLA-presented peptidome reflects the status of the cellular proteome, hence disease-related aberrations of post-translational modifications (PTMs) might lead to presentation of peptides harboring PTMs. Therefore, characterization of HLA-bound PTM peptides could shed light on their relevance in immune and disease processes. In this issue, Ramarathinam et al. investigate the presentation of HIV envelope (HIVenv) peptides bound to the HLA-B*57:01 allele. Among these peptides, the authors specifically focused on a kynurenine modified peptide. To this end, they characterize the possible origin of the kynurenine modification, its effect on HLA binding affinity, stability, conformation within the complex and its immunogenicity compared to the native counterpart. This article is protected by copyright. All rights reserved
    Print ISSN: 1615-9853
    Electronic ISSN: 1615-9861
    Topics: Medicine
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  • 50
    Publication Date: 2018-03-09
    Description: Signal transduction cascades governed by kinases and GTPases are a critical component of the command and control of cellular processes, with the precise outcome partly determined by direct protein-protein interactions (PPIs). Here, we use the human ROCO proteins as a model for investigating PPI signalling events – taking advantage of the unique dual kinase/GTPase activities and scaffolding properties of these multidomain proteins. We report PPI networks that encompasses the human ROCO proteins, developed using two complementary approaches. First, using our recently developed weighted PPI network analysis (WPPINA) pipeline, a confidence-weighted overview of validated ROCO protein interactors was obtained from peer-reviewed literature. Second, novel ROCO PPIs were assessed experimentally via protein microarray screens. We compared the networks derived from these orthologous approaches to identify common elements within the ROCO protein interactome; functional enrichment analysis of this common core of the network identified stress response and cell projection organisation as shared functions within this protein family. Despite the presence of these commonalities, our results suggest that many unique interactors and therefore some specialised cellular roles have evolved for different members of the ROCO proteins. Overall, this multi-approach strategy to increase the resolution of protein interaction networks represents a prototype for the utility of PPI data integration in understanding signalling biology. This article is protected by copyright. All rights reserved
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    Electronic ISSN: 1615-9861
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  • 51
    Publication Date: 2018-03-12
    Description: A pathogenic connection between autoreactive T cells, fungal infection, and carcinogenesis has been demonstrated in studies of human autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) as well as in a mouse model in which kinase-dead Ikkα knock-in mice develop impaired central tolerance, autoreactive T cell–mediated autoimmunity, chronic fungal infection, and esophageal squamous cell carcinoma, which recapitulates APECED. IκB kinase α (IKKα) is one subunit of the IKK complex required for NF-κB activation. IKK/NF-κB is essential for central tolerance establishment by regulating the development of medullary thymic epithelial cells (mTECs) that facilitate the deletion of autoreactive T cells in the thymus. In this review, we extensively discuss the pathogenic roles of inborn errors in the IKK/NF-κB loci in the phenotypically related diseases APECED, immune deficiency syndrome, and severe combined immunodeficiency; differentiate how IKK/NF-κB components, through mTEC (stroma), T cells/leukocytes, or epithelial cells, contribute to the pathogenesis of infectious diseases, autoimmunity, and cancer; and highlight the medical significance of IKK/NF-κB in these diseases. IKK/NF-κB regulates the expression of many genes that encode proteins involved in many crucial biological functions, such as immunity, tissue homeostasis, and fungal/bacterial/viral infections. Also, IKKα plays anti-tumor activities in many organs independently of NF-κB pathways. Thus, an inborn error in one of these gene loci can cause severe human diseases through these complicated mechanisms.
    Print ISSN: 0265-9247
    Electronic ISSN: 1521-1878
    Topics: Biology , Medicine
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  • 52
    Publication Date: 2018-03-12
    Description: Stomatin-like protein 2 (STOML2 or SLP-2) is an oncogenic anti-apoptotic protein that is up-regulated in several types of cancer, including cervical cancer. However, the mechanisms responsible for the SLP-2 anti-apoptotic function remain poorly understood. Here, we show that siRNA-mediated SLP-2 suppression decreases growth of human cervical cancer HELA and SIHA cells, and increases cisplatin-induced apoptosis through activation of MEK/ERK signaling and suppression of the mitochondrial pathway. The inhibition of the mitochondrial pathway is mediated by increasing the mitochondrial Ca 2+ concentration and mitochondrial membrane potential, thereby downregulating p-MEK and p-ERK levels, upregulating the Bax/Bcl-2 ratio, increasing cytochrome C release from mitochondria into the cytosol, and upregulating levels of cleaved-caspase 9, cleaved-caspase 3 and cleaved-PARP. SLP-2 overexpression using adenovirus-STOML2 has the opposite effect: it upregulates p-MEK and p-ERK and downregulates the Bax/Bcl-2 ratio and levels of cleaved-caspase 9 to caspase 9, cleaved-caspase 3 to caspase 3, and cleaved-PARP to PARP in cisplatin-treated cells. These data show that SLP-2 inhibits the cisplatin-induced apoptosis by activating the MEK/ERK signaling and inhibiting the mitochondrial apoptosis pathway in cervical cancer cells. This article is protected by copyright. All rights reserved.
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  • 53
    Publication Date: 2018-03-12
    Description: The aim of this study was to develop a new methodology that is suitable for DNA methylation diagnostics and to demonstrate its clinical applicability. We developed a new anion-exchange column for high-performance liquid chromatography (HPLC) with electrostatic and hydrophobic properties. Both cytosine and thymine, corresponding to methylated and unmethylated cytosine after bisulfite modification, respectively, are captured by electrostatic interaction and then discriminated from each other by their hydrophobic interactions. The DNA methylation levels of synthetic DNAs were quantified accurately and reproducibly within 10 minutes without time-consuming pretreatment of PCR products, and the measured values were unaffected by the distribution of methylated CpGs within the synthetic DNA fragments. When the DNA methylation status of the FAM150A gene, a marker of the CpG island methylator phenotype specific to clear cell renal cell carcinoma (ccRCC), was examined in 98 patients with ccRCCs, bulk specimens of tumorous tissue including cancer cells showing DNA methylation of the FAM150A gene were easily identifiable by simply viewing the differentiated chromatograms, even when the cancer cell content was low. Sixteen ccRCCs showing DNA methylation more frequently exhibited clinicopathological parameters reflecting tumor aggressiveness, i.e. a larger diameter, higher histological grade, vascular involvement, renal vein tumor thrombi, infiltrating growth, tumor necrosis, renal pelvis invasion and higher pathological Tumor-Node-Metastasis stage, and had significantly lower recurrence-free and overall survival rates. These data indicate that HPLC analysis using this newly developed anion-exchange column can be a powerful tool for DNA methylation diagnostics, including prognostication of patients with cancers, in a clinical setting. This article is protected by copyright. All rights reserved.
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  • 54
    Publication Date: 2018-03-12
    Description: Approximately 75% of cutaneous rosacea patients also suffer from an ocular involvement with blepharitis and meibomian gland dysfunction often presented as chalazia. Clinical symptoms are foreign body sensation, light sensitivity, burning and tearing. This article is protected by copyright. All rights reserved.
    Print ISSN: 0007-0963
    Electronic ISSN: 1365-2133
    Topics: Medicine
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  • 55
    Publication Date: 2018-03-12
    Description: Ectodermal dysplasia (ED) is a heterogeneous group of disorders caused by mutations in at least thirteen genes. Recently, a study reported Palestinian patients with ED from consanguineous families with a homozygous mutation in KREMEN1 (Kringle-containing transmembrane protein 1) and proposed it to be a causative gene for the autosomal recessive ED 13, hair/tooth type (ECTD13; OMIM #617392). A Thai family, parents and two children affected with ED, was recruited. The study was exempted from review by the Institutional Review Board, Faculty of Medicine, Chulalongkorn University (IRB584/60). Written informed consents of each participant were obtained according to the Declaration of Helsinki. Mutation analyses were performed as described previously. This article is protected by copyright. All rights reserved.
    Print ISSN: 0007-0963
    Electronic ISSN: 1365-2133
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  • 56
    Publication Date: 2018-03-12
    Description: Psoriasis is a prevalent chronic inflammatory disease associated with comorbidities, e.g. cardiometabolic diseases, inflammatory bowel disease, and depression that may share an inflammatory origin. Smoking increases the risk of psoriasis and the disease has also been linked to chronic obstructive pulmonary disease (COPD) and asthma, with evidence of shared inflammatory cytokine-mediated mechanisms. Moreover, subjects with psoriasis display increased risk of infections, especially respiratory infections including pneumonia. However, only a small single-center study of pulmonary function in subjects with psoriasis is available. This article is protected by copyright. All rights reserved.
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  • 57
    Publication Date: 2018-03-12
    Print ISSN: 0007-0963
    Electronic ISSN: 1365-2133
    Topics: Medicine
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  • 58
    Publication Date: 2018-03-12
    Description: It is generally accepted that insulin exerts an antiapoptotic effect against ischemia/reperfusion through the activation of PI3K/Akt/mTOR pathway. MicroRNAs involve in multiple cardiac pathophysiological processes, including ischemia/reperfusion–induced cardiac injury. However, the regulation of microRNAs in the cardioprotective effect of insulin is rarely discussed. In this study, using a cell model of ischemia through culturing H9C2 cardiac myocytes in serum-free medium with hypoxia, we demonstrated that pretreatment with insulin significantly inhibited cell apoptosis and downregulated microRNA-320 (miR-320) expression. Interestingly, miR-320 mimic impaired the cardioprotective effect of insulin against myocardial ischemia injury by targeting survivin, which is a member of the family of inhibitor of apoptosis proteins. Suppression miR-320 expression by miR-320 inhibitor in H9C2 cells with myocardial ischemia mimics the cardioprotective effect of insulin by maintaining survivin expression. Taken together, miR-320–mediated survivin expression involves in cardioprotective effect of insulin against myocardial ischemia injury. Significance of this study Myocardial ischemia/reperfusion (I/R) injury remains an important clinical problem with extremely deficient clinical therapies. Insulin exerts an antiapoptotic effect against I/R through the activation of PI3K/Akt/mTOR pathway. Here, we provided evidences to show that microRNA-320 involves in the cardioprotective effect of insulin by targeting survivin, which is an inhibitor of apoptosis protein and functions as a key regulator in cell apoptosis and involves in the tumour genesis and progression. Our findings may provide a new potential therapeutic strategy for I/R injury and ischemic heart disease.
    Print ISSN: 0263-6484
    Electronic ISSN: 1099-0844
    Topics: Biology , Medicine
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  • 59
    Publication Date: 2018-03-12
    Description: Enzymes belonging to the aspartase/fumarase superfamily catalyze elimination of various functional groups from succinate derivatives and play an important role in primary metabolism and aromatic compound degradation. Recently, an aspartase/fumarase superfamily enzyme, CreD, was discovered in cremeomycin biosynthesis. This enzyme catalyzes the elimination of nitrous acid from nitrosuccinate synthesized from aspartate by CreE, a flavin-dependent monooxygenase. Nitrous acid generated by this pathway is an important precursor of the diazo group of cremeomycin. CreD is the first aspartase/fumarase superfamily enzyme that was reported to catalyze the elimination of nitrous acid, and therefore we aimed to analyze its reaction mechanism. The crystal structure of CreD was determined by the molecular replacement native-single anomalous diffraction (MR native-SAD) method at 2.18 Å resolution. Subsequently, the CreD-fumarate complex structure was determined at 2.30 Å resolution by the soaking method. Similar to other aspartase/fumarase superfamily enzymes, the crystal structure of CreD was composed of three domains and formed a tetramer. Two molecules of fumarate were observed in one subunit of the CreD-fumarate complex. One of them was located in the active site pocket formed by three different subunits. Intriguingly, no histidine residue, which usually functions as a catalytic acid in aspartase/fumarase superfamily enzymes, was found around the fumarate molecule in the active site. Based on the mutational analysis, we propose a catalytic mechanism of CreD, in which Arg325 acts as a catalytic acid. This article is protected by copyright. All rights reserved.
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 60
    Publication Date: 2018-03-12
    Description: Tumor necrosis factor (TNF)-α activates a diverse array of signaling pathways in vascular endothelial cells (ECs), leading to the inflammatory phenotype that contributes to the vascular dysfunction and neutrophil emigration in patients with sepsis. To date, it is not well understood what key regulator might coordinate signaling pathways to achieve inflammatory response in TNF-α-stimulated ECs. This study investigated the role of dual specificity phosphatase-6 (DUSP6) in the regulation of endothelial inflammation. Using knockout mice, we found that DUSP6 is important for TNF-α-induced endothelial intercellular adhesion molecule-1 (ICAM-1) expression in aorta and in vein. Moreover, genetic deletion of Dusp6 in pulmonary circulation significantly alleviated the susceptibility of mice to lung injury caused by neutrophil recruitment during experimental sepsis induced by TNF-α or lipopolysaccharide (LPS). The role of DUSP6 was further investigated in primary human umbilical vein endothelial cells (HUVECs). Employing RNAi approach in which endogenous DUSP6 was ablated, we showed a critical function of DUSP6 to facilitate TNF-α-induced ICAM-1 expression and endothelial leukocyte interaction. Interestingly, DUSP6-promoted endothelial inflammation is independent of extracellular signaling-regulated kinase (ERK) signaling. On the other hand, inducible DUSP6 leads to activation of canonical nuclear factor (NF)-κB-mediated transcription of ICAM-1 gene in TNF-α-stimulated human ECs. These results are the first to demonstrate a positive role of DUSP6 in endothelial inflammation-mediated pathological process and the underlying mechanism through which DUSP6 promotes NF-κB signaling in the inflamed ECs. Our findings suggest that manipulation of DUSP6 holds great potential for the treatment of acute inflammatory diseases. This article is protected by copyright. All rights reserved.
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 61
  • 62
    Publication Date: 2018-03-12
    Description: The discovery of new therapeutic drugs with the ability of preventing inflammation and joint destruction with less adverse effects is urgently needed for rheumatoid arthritis (RA). Carnosic acid (CA), a major phenolic compound isolated from the leaves of Rosemary ( Rosmarinus officinalis L .), has been reported to have antioxidative and antimicrobial properties. However, its effects on RA have not been elucidated. Here, we investigated the effects of CA on osteoclasts and fibroblast-like synoviocytes in vitro and on collagen-induced arthritis (CIA) in Wistar rats in vivo. Our in vitro and in vivo studies showed that CA suppressed the expression of pro-inflammatory cytokines including TNFɑ , IL-1β , IL-6 , IL-8 , IL-17 and MMP-3 , and downregulated the production of RANKL . More importantly, we observed that CA inhibited osteoclastogenesis and bone resorption in vitro and exerted therapeutic protection against joint destruction in vivo. Further biochemical analysis demonstrated that CA suppressed RANKL-induced activations of NF-κB and MAPKs (JNK and p38) leading to the downregulation of NFATc1. Taken together, our findings provide the convincing evidence that rosemary derived CA is a promising natural compound for the treatment of RA. Our in vitro and in vivo studies revealed that carnosic acid (CA) could effectively suppress the production of cytokines in TNFα-induced RA-FLS and CIA rats. More importantly, we found that CA significantly inhibited osteoclastogenesis and bone resorption in vitro and exerted therapeutic protection against joint destruction in vivo. Thus, CA has the potential to be researched and developed into a novel therapeutic natural agent for treatment of human rheumatoid arthritis.
    Electronic ISSN: 1097-4652
    Topics: Biology , Medicine
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  • 63
    Publication Date: 2018-03-12
    Description: microRNAs (miRNAs) are small non-coding RNAs that regulate gene expression post-transcriptionally by interfering with the translation of one or more target mRNAs. The unique miRNA sequences are involved in many physiological and pathological processes. Dysregulation of miRNAs contributes to the pathogenesis of all types of cancer. Notably, the diminished expression of tumor suppressor miRNAs, such as members of the Let-7 and miR-34 family, promotes tumor progression, invasion and metastasis. The past lustrum in particular, has witnessed substantial improvement of miRNA replacement therapy. This approach aims to restore tumor suppressor miRNA function in tumor cells using synthetic miRNA mimics or miRNA expression plasmids. Here, we provide a comprehensive review of recent advances in miRNA replacement therapy for treatment of cancer and its advantages over conventional gene therapy. We discuss a wide variety of delivery methods and vectors, as well as obstacles that remain to be overcome. Lastly, we review efforts to reverse epigenetic alterations, which affect miRNA expression in cancer cells, and the promising observation that restoring miRNA function re-sensitizes resistant tumor cells to chemotherapeutic drugs. The fact that various miRNA replacement therapies are currently in clinical trial demonstrates the great potential of this approach to treat cancer. Recent advances in microRNA replacement therapy in cancers.
    Electronic ISSN: 1097-4652
    Topics: Biology , Medicine
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  • 64
    Publication Date: 2018-03-12
    Description: Purpose This study demonstrates a DCE-MRI estimate of tumor interstitial fluid pressure (TIFP) and hydraulic conductivity in a rat model of glioblastoma, with validation against an invasive wick-in-needle (WIN) technique. An elevated TIFP is considered a mark of aggressiveness, and a decreased TIFP a predictor of response to therapy. Methods The DCE-MRI studies were conducted in 36 athymic rats (controls and posttreatment animals) with implanted U251 cerebral tumors, and with TIFP measured using a WIN method. Using a model selection paradigm and a novel application of Patlak and Logan plots to DCE-MRI data, the MRI parameters required for estimating TIFP noninvasively were estimated. Two models, a fluid-mechanical model and a multivariate empirical model, were used for estimating TIFP, as verified against WIN-TIFP. Results Using DCE-MRI, the mean estimated hydraulic conductivity (MRI-K) in U251 tumors was (2.3 ± 3.1) × 10 −5 (mm 2 /mmHg-s) in control studies. Significant positive correlations were found between WIN-TIFP and MRI-TIFP in both mechanical and empirical models. For instance, in the control group of the fluid-mechanical model, MRI-TIFP was a strong predictor of WIN-TIFP (R 2  = 0.76, p  〈 .0001). A similar result was found in the bevacizumab-treated group of the empirical model (R 2  = 0.93, p  = .014). Conclusion This research suggests that MRI dynamic studies contain enough information to noninvasively estimate TIFP in this, and possibly other, tumor models, and thus might be used to assess tumor aggressiveness and response to therapy.
    Print ISSN: 0740-3194
    Electronic ISSN: 1522-2594
    Topics: Medicine
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  • 65
    Publication Date: 2018-03-12
    Description: Purpose To develop a rapid segmentation-free method to visualize and compute wall shear stress (WSS) throughout the aorta using 4D Flow MRI data. WSS is the drag force-per-area the vessel endothelium exerts on luminal blood; abnormal levels of WSS are associated with cardiovascular pathologies. Previous methods for computing WSS are bottlenecked by labor-intensive manual segmentation of vessel boundaries. A rapid automated segmentation-free method for computing WSS is presented. Theory and Methods Shear stress is the dot-product of the viscous stress tensor and the inward normal vector. The inward normal vectors are approximated as the gradient of fluid speed at every voxel. Subsequently, a 4D map of shear stress is computed as the partial derivatives of velocity with respect to the inward normal vectors. We highlight the shear stress near the wall by fusing visualization with edge-emphasized anatomical data. Results As a proof-of-concept, four cases with aortic pathologies are presented. Visualization allows for rapid localization of pathologic WSS. Subsequent analysis of these pathological regions enables quantification of WSS. Average WSS during peak systole measures approximately 50–60 cPa in nonpathological regions of the aorta and is elevated in regions of stenosis, coarctation, and dissection. WSS is reduced in regions of aneurysm. Conclusion A volumetric technique for calculation and visualization of WSS from 4D Flow MRI data is presented. Traditional labor-intensive methods for WSS rely on explicit manual segmentation of vessel boundaries before visualization. This automated volumetric strategy for visualization and quantification of WSS may facilitate its clinical translation.
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    Electronic ISSN: 1522-2594
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  • 66
    Publication Date: 2018-03-12
    Description: Purpose To develop a new MRI technique to rapidly measure exchange rates in CEST MRI. Methods A novel pulse sequence for measuring chemical exchange rates through a progressive saturation recovery process, called PRO-QUEST (progressive saturation for quantifying exchange rates using saturation times), has been developed. Using this method, the water magnetization is sampled under non-steady-state conditions, and off-resonance saturation is interleaved with the acquisition of images obtained through a Look-Locker type of acquisition. A complete theoretical framework has been set up, and simple equations to obtain the exchange rates have been derived. Results A reduction of scan time from 58 to 16 minutes has been obtained using PRO-QUEST versus the standard QUEST. Maps of both T 1 of water and B 1 can simply be obtained by repetition of the sequence without off-resonance saturation pulses. Simulations and calculated exchange rates from experimental data using amino acids such as glutamate, glutamine, taurine, and alanine were compared and found to be in good agreement. The PRO-QUEST sequence was also applied on healthy and infarcted rats after 24 hours, and revealed that imaging specificity to ischemic acidification during stroke was substantially increased relative to standard amide proton transfer–weighted imaging. Conclusion Because of the reduced scan time and insensitivity to nonchemical exchange factors such as direct water saturation, PRO-QUEST can serve as an excellent alternative for researchers and clinicians interested to map pH changes in vivo.
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    Topics: Medicine
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  • 67
    Publication Date: 2018-03-12
    Description: Purpose Dixon-based fat suppression has recently gained interest for dynamic contrast-enhanced MRI, but multi-echo techniques require longer scan times and reduce temporal resolution compared to single-echo alternatives without fat suppression. The purpose of this work is to demonstrate accelerated single-echo Dixon imaging with high spatial and temporal resolution. Theory and Methods Real-valued water and fat images can be obtained from a single measurement if the shared initial phase and that due to are assumed known a priori. An expression for simultaneous sensitivity encoding (SENSE) unfolding and fat-water separation is derived for the general undersampling case, and simplified under the special case of uniform Cartesian undersampling. In vivo experiments were performed in extremities and brain with SENSE acceleration factors of up to R  = 8. Results Single-echo Dixon reconstruction of highly undersampled data was successfully demonstrated. Dynamic contrast-enhanced water and fat images provided high spatial and temporal resolution dynamic images with image update times shorter than previous single-echo Dixon work. Conclusion Time-resolved contrast-enhanced MRI with single-echo Dixon fat suppression shows high image quality, improved vessel delineation, and reduced sensitivity to motion when compared to time-subtraction methods.
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  • 68
    Publication Date: 2018-03-12
    Description: Purpose We introduce the quantitative, continuous marker cartilage cavity that quantifies cartilage lesions by the total lesion volume. The aim was to quantify small lesions as well as large, full-depth lesions. Methods We included 315 knees from the Center for Clinical and Basic Research (CCBR), 972 knees from the Osteoarthritis Initiative (OAI), and 791 knees from the Prevention of OA in Overweight Females (PROOF) cohorts. In a subset, we digitally inserted artificial lesions. Each knee MRI was segmented using the knee imaging quantification (KIQ) framework. We quantified cartilage mean thickness and cavity from high-resolution cartilage thickness maps. Finally, we quantified lesion volume by the gradient peak method (GPM). Results Scan–rescan precision for cartilage cavity was 7.1%/3.0%. The cartilage cavity accuracy on the artificial lesions was determined as linear correlation at 0.88 with an average 8% under-estimation of lesion volume. Cavity and degree of radiographic osteoarthritis (ROA) correlated for all compartments (Spearman's rho between 0.14–0.56, P  〈 0.001). Cavity had modest correlations to whole-organ magnetic resonance imaging score (WORMS) cartilage lesion scores but strong correlations with Boston-Leeds osteoarthritis knee score (BLOKS)/MRI osteoarthritis knee score (MOAKS) scores in most compartments (rho between 0.08–0.65, P  〈 0.001). Cavity correlated with WOMAC pain for all tibio-femoral compartments in OAI (rho between 0.19–0.25, P  〈 0.001) and most compartments in PROOF. Comparing with the GPM estimate, cavity was more precise, more accurate, and correlated stronger with ROA, lesion scores, and pain levels. Conclusion The strong correlations with ROA, radiologist lesion scores, and pain demonstrated that cavity captured OA and lesion features. Thereby, it may be appropriate for quantification of cartilage surface irregularity.
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  • 69
    Publication Date: 2018-03-12
    Description: Purpose To reconstruct artifact-free images from measured k-space data, when the actual k-space trajectory deviates from the nominal trajectory due to gradient imperfections. Methods Trajectory errors arising from eddy currents and gradient delays introduce phase inconsistencies in several fast scanning MR pulse sequences, resulting in image artifacts. The proposed algorithm provides a novel framework to compensate for this phase distortion. The algorithm relies on the construction of a multi-block Hankel matrix, where each block is constructed from k-space segments with the same phase distortion. In the presence of spatially smooth phase distortions between the segments, the complete block-Hankel matrix is known to be highly low-rank. Since each k-space segment is only acquiring part of the k-space data, the reconstruction of the phase compensated image from their partially parallel measurements is posed as a structured low-rank matrix optimization problem, assuming the coil sensitivities to be known. Results The proposed formulation is tested on radial acquisitions in several settings including partial Fourier and golden-angle acquisitions. The experiments demonstrate the ability of the algorithm to successfully remove the artifacts arising from the trajectory errors, without the need for trajectory or phase calibration. The quality of the reconstruction was comparable to corrections achieved using the Trajectory Auto-Corrected Image Reconstruction (TrACR) for radial acquisitions. Conclusion The proposed method provides a general framework for the recovery of artifact-free images from radial trajectories without the need for trajectory calibration.
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  • 70
    Publication Date: 2018-03-12
    Description: Purpose 3D time-resolved (4D) phase contrast MRI can be used to study muscle contraction. However, 3D coverage with sufficient spatiotemporal resolution can only be achieved by interleaved acquisitions during many repetitions of the motion task, resulting in long scan times. The aim of this study was to develop a compressed sensing accelerated 4D phase contrast MRI technique for quantification of velocities and strain rate of the muscles in the lower leg during active plantarflexion/dorsiflexion. Methods Nine healthy volunteers were scanned during active dorsiflexion/plantarflexion task. For each volunteer, we acquired a reference scan, as well as 4 different accelerated scans (k-space undersampling factors: 3.14X, 4.09X, 4.89X, and 6.41X) obtained using Cartesian Poisson disk undersampling schemes. The data was reconstructed using a compressed sensing pipeline. For each scan, velocity and strain rate values were quantified in the gastrocnemius lateralis, gastrocnemius medialis, tibialis anterior, and soleus. Results No significant differences in velocity values were observed as a function acceleration factor in the investigated muscles. The strain rate calculation resulted in one positive (s + ) and one negative (s − ) eigenvalue, whereas the third eigenvalue (s 3 ) was consistently 0 for all the acquisitions. No significant differences were observed for the strain rate eigenvalues as a function of acceleration factor. Conclusions Data undersampling combined with compressed sensing reconstruction allowed obtainment of time-resolved phase contrast acquisitions with 3D coverage and quantitative information comparable to the reference scan. The 3D sensitivity of the method can help in understanding the connection between muscle architecture and muscle function in future studies.
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  • 71
    Publication Date: 2018-03-12
    Description: Purpose To map the cerebral metabolic rate of oxygen (CMRO 2 ) by estimating the oxygen extraction fraction (OEF) from gradient echo imaging (GRE) using phase and magnitude of the GRE data. Theory and Methods 3D multi-echo gradient echo imaging and perfusion imaging with arterial spin labeling were performed in 11 healthy subjects. CMRO 2 and OEF maps were reconstructed by joint quantitative susceptibility mapping (QSM) to process GRE phases and quantitative blood oxygen level-dependent (qBOLD) modeling to process GRE magnitudes. Comparisons with QSM and qBOLD alone were performed using ROI analysis, paired t-tests, and Bland-Altman plot. Results The average CMRO 2 value in cortical gray matter across subjects were 140.4 ± 14.9, 134.1 ± 12.5, and 184.6 ± 17.9 μmol/100 g/min, with corresponding OEFs of 30.9 ± 3.4%, 30.0 ± 1.8%, and 40.9 ± 2.4% for methods based on QSM, qBOLD, and QSM+qBOLD, respectively. QSM+qBOLD provided the highest CMRO 2 contrast between gray and white matter, more uniform OEF than QSM, and less noisy OEF than qBOLD. Conclusion Quantitative CMRO 2 mapping that fits the entire complex GRE data is feasible by combining QSM analysis of phase and qBOLD analysis of magnitude.
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  • 72
    Publication Date: 2018-03-12
    Description: Purpose 2D turbo-spin-echo (TSE) is widely used in the clinic for neuroimaging. However, the long refocusing radiofrequency pulse train leads to high specific absorption rate (SAR) and alters the contrast compared to conventional spin-echo. The purpose of this work is to develop a robust 2D spiral TSE technique for fast T 2 -weighted imaging with low SAR and improved contrast. Methods A spiral-in/out readout is incorporated into 2D TSE to fully take advantage of the acquisition efficiency of spiral sampling while avoiding potential off-resonance-related artifacts compared to a typical spiral-out readout. A double encoding strategy and a signal demodulation method are proposed to mitigate the artifacts because of the T 2 -decay-induced signal variation. An adapted prescan phase correction as well as a concomitant phase compensation technique are implemented to minimize the phase errors. Results Phantom data demonstrate the efficacy of the proposed double encoding/signal demodulation, as well as the prescan phase correction and concomitant phase compensation. Volunteer data show that the proposed 2D spiral TSE achieves fast scan speed with high SNR, low SAR, and improved contrast compared to conventional Cartesian TSE. Conclusion A robust 2D spiral TSE technique is feasible and provides a potential alternative to conventional 2D Cartesian TSE for T 2 -weighted neuroimaging.
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  • 73
    Publication Date: 2018-03-12
    Description: Purpose To develop a rapid, non-CPMG high-resolution volumetric imaging approach, exhibiting a speed and in-plane resilience to field inhomogeneities comparable to RARE/turbo-spin-echo (TSE) while endowed with unique downsampling characteristics. Methods A multi-scan extension of cross-term spatiotemporal encoding (xSPEN) is introduced and analyzed. The method simultaneously yields k y / k z data containing low and high frequency components, as well as transposed, low-resolution z / y images. This dual k -/spatial-domain information is captured by a multi-scan procedure that phase-encodes k y while simultaneously slice-selecting z . A reconstruction scheme converting this information into high resolution 3D images with fully multiplexed volumetric coverage is introduced and exemplified. Results Phase-encoded xSPEN was tested by human brain imaging at sub-mm resolutions. The method exceeded 2D TSE's sensitivity by factors of ≈3–4, while providing similar resolution and SNR as 3D TSE in ≈50% acquisition times. The method's contrast is dominated by T 2 and is free from “bright-fat” effects associated to spin-echo trains. Further acceleration is enabled by the method's downsampling abilities. Tradeoffs between encoding time, number of measurements, spatial resolution, SNR, and artifact levels are also laid out. Conclusion A new MRI strategy is introduced delivering high in- and through-plane resolutions while enjoying full Fourier multiplexing, leading to fast acquisitions with high SNR.
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  • 74
    Publication Date: 2018-03-12
    Description: ABSTRACT Nickel (Ni) is an environmental and occupational carcinogen, and exposure to Ni is associated with lung and nasal cancers in humans. Furthermore, Ni exposure is implicated in several lung diseases including chronic inflammatory airway diseases, asthma and fibrosis. However, the mutagenic potential of Ni is low and does not correlate with its potent toxicity and carcinogenicity. Therefore, mechanisms underlying Ni exposure-associated diseases remain poorly understood. Since the health risks of environmental exposures often continue post exposure, understanding the exposure effects that persist after the termination of exposure could provide mechanistic insights into diseases. By examining the persistent effects of Ni exposure, we report that Ni induces epithelial-mesenchymal transition (EMT) and that the mesenchymal phenotype remains irreversible even after the termination of exposure. Ni-induced EMT was dependent on the irreversible upregulation of ZEB1, an EMT master regulator, via resolution of its promoter bivalency. ZEB1, upon activation, downregulated its repressors as well as the cell-cell adhesion molecule, E-cadherin, resulting in the cells undergoing EMT and switching to persistent mesenchymal status. ZEB1 depletion in cells exposed to Ni attenuated Ni-induced EMT. Moreover, Ni exposure did not induce EMT in ZEB1-depleted cells. Activation of EMT, during which the epithelial cells lose cell-cell adhesion and become migratory and invasive, plays a major role in asthma, fibrosis, and cancer and metastasis, lung diseases associated with Ni exposure. Therefore, our finding of irreversible epigenetic activation of ZEB1 by Ni exposure and the acquisition of persistent mesenchymal phenotype would have important implications in understanding Ni-induced diseases. This article is protected by copyright. All rights reserved
    Print ISSN: 0899-1987
    Electronic ISSN: 1098-2744
    Topics: Medicine
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  • 75
    Publication Date: 2018-03-12
    Description: Squamous cell carcinoma of head and neck (SCCHN) is one of the most common malignancies worldwide, and nucleotide excision repair (NER) is involved in SCCHN susceptibility. In this analysis of 349 newly diagnosed SCCHN patients and 295 cancer-free controls, we investigated whether expression levels of eight core NER proteins were associated with risk of SCCHN. We quantified NER protein expression levels in cultured peripheral lymphocytes using a reverse-phase protein microarray. Compared with the controls, SCCHN patients had statistically significantly lower expression levels of ERCC3 and XPA ( P  = 0.001 and 0.001, respectively). After dividing the subjects by controls' median values of expression levels, we found a dose-dependent association between an increased risk of SCCHN and low expression levels of ERCC3 (adjusted OR, 1.75 and 95% CI: 1.26-2.42; P trend  = 0.008) and XPA (adjusted OR, 1.88; 95% CI, 1.35-2.60; P trend  = 0.001). We also identified a significant multiplicative interaction between smoking status and ERCC3 expression levels ( P  = 0.014). Finally, after integrating demographic and clinical variables, we found the addition of ERCC3 and XPA expression levels to the model significantly improved the sensitivity of the expanded model on SCCHN risk. In conclusion, reduced protein expression levels of ERCC3 and XPA were associated with an increased risk of SCCHN. However, these results need to be confirmed in additional large studies. This article is protected by copyright. All rights reserved
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  • 76
    Publication Date: 2018-03-13
    Description: Chris S Earl, Teh Wooi Keong, Shi-qi An, Sarah Murdoch, Yvonne McCarthy, Junkal Garmendia, Joseph Ward, J Maxwell Dow, Liang Yang, George A O'Toole & Robert P Ryan The above article, published May 20 2015 in EMBO Molecular Medicine , has been retracted by agreement between the authors of the study, CSE, TWK, SQA, SM, YMcC, JG, JW, JMD, LY, RPR, the journal Chief Editor and the EMBO Head of Scientific Publications in accordance with the outcomes of independent investigations conducted by the University of Dundee and University College Cork. GAO'T disagrees with the text of this retraction notice, albeit not with the retraction. The following issues are noted: Table 1 contains clinical data described in the paper as being derived from a cohort of asthma patients. However, the provenance of this data is unclear. Based on the evidence available, the University of Dundee investigation concluded that the majority of the patient cohort is likely to be a subset of a cohort of cystic fibrosis patients reported in PLoS One 8(12): e82432 ( https://doi.org/10.1371/journal.pone.0082432 ), although in a number of cases the patient's gender is at odds between the two reports. The RNAseq data are unavailable on the European Nucleotide Archive under the reported accession number ERG003569. RNAseq data were uploaded with accession number ERS654066 before publication. The paper describes use of both prednisolone and prednisone, yet only the latter was used in the study.
    Print ISSN: 1757-4676
    Electronic ISSN: 1757-4684
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