Your email was sent successfully. Check your inbox.

An error occurred while sending the email. Please try again.

Proceed reservation?

Export
Filter
  • Wiley-Blackwell  (474,673)
  • American Institute of Physics (AIP)  (154,286)
Collection
Years
  • 1
    Publication Date: 2018-01-03
    Description: This paper reviews the results of experiments underway since 1950 studying the solid solubility of n-alkanes (from ethane up to n-triacontane) in methane and the factors influencing the global phase equilibrium behavior of the related binary mixtures. The methodology used consists of a series of comparisons of data in the composition-temperature and pressure-temperature diagrams. The kind of global phase diagram of the binary mixtures of methane referred to in the present article is found to be dependent of the ratio between the triple-point temperature of the generic n-alkane and the critical-point temperature of methane. The Peng-Robinson (1976), Predictive Soave-Redlich-Kwong, and Predictive Peng-Robinson (1978) equations of state have been applied and compared with respect to the calculation of bivariant, univariant, and invariant equilibrium data involving solid n-alkanes in binary mixture with methane. The fugacities of the solid n-alkanes have been calculated by means of the so-called classic approach. This article is protected by copyright. All rights reserved.
    Print ISSN: 0001-1541
    Electronic ISSN: 1547-5905
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Signatur Availability
    BibTip Others were also interested in ...
  • 2
    Publication Date: 2018-01-03
    Description: ABSTRACT The CO 2 solubility data in the ionic liquid (IL) 1-allyl-3-methylimidazolium bis(trifluoromethyl sulfonyl)imide, methanol (MeOH), and their mixture with different combinations at temperatures of (313.2, 333.2, and 353.2 K) and pressures up to 6.50 MPa were measured experimentally. New group binary interaction parameters of the predictive UNIFAC-Lei model, which has been continually advanced by our group, were introduced by correlating the experimental data of this work and the literature. The consistency between experimental data and predicted results proves the reliability of UNIFAC-Lei model for CO 2 -IL-organic solvent systems. The newly obtained parameters were incorporated into the UNIFAC property model of Aspen Plus software to optimize a conceptual process developed for the purification of a CO 2 -containing gas stream. The simulation results indicate that the use of IL either mixed with MeOH or purely considerably lowers the process power consumption, and improves the process performance in terms of CO 2 capture rate and solvent loss. This article is protected by copyright. All rights reserved.
    Print ISSN: 0001-1541
    Electronic ISSN: 1547-5905
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Signatur Availability
    BibTip Others were also interested in ...
  • 3
  • 4
    Publication Date: 2018-01-03
    Description: In 2008, a new species for the French bee fauna was recorded in Allauch near Marseille: the giant resin bee, Megachile sculpturalis (Smith, 1853). This was the first European record of this species that is native to East Asia. To our knowledge, it is the first introduced bee species in Europe. Here, we provide an overview of the current distribution of M. sculpturalis in France and we describe the history of its range expansion. Besides our own observations, information was compiled from literature and Internet websites, and by contacting naturalist networks. We collected a total of 117 records ( locality  ×  year combinations) for the 2008–2016 period. The geographical range of M. sculpturalis has extended remarkably, now occupying a third of continental France, with the most northern and western records located 335 and 520 km from Allauch, respectively. Information on its phenology, feeding, and nesting behavior is also provided. We report several events of nest occupation or eviction of Osmia sp. and Xylocopa sp. individuals by M. sculpturalis . Our results show that M. sculpturalis is now well established in France. Given its capacity to adapt and rapidly expand its range, we recommend amplifying the monitoring of this species to better anticipate the changes in its geographical range and its potential impacts on native bees. In 2008, a new species for the French bee fauna was recorded in Allauch near Marseille: the giant resin bee, Megachile sculpturalis (Smith, 1853). This was the first European record of this species native from East Asia. Here, we provide an overview of the current distribution of M. sculpturalis in France and we describe its expansion history.
    Electronic ISSN: 2045-7758
    Topics: Biology
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 5
    Publication Date: 2018-01-03
    Description: Severe heart pathology upon virus infection is closely associated with the immunological equipment of the host. Since there is no specific treatment available, current research focuses on identifying new drug targets to positively modulate predisposing immune factors. Utilizing a murine model with high susceptibility to coxsackievirus B3-induced myocarditis, this study describes ONX 0914—an immunoproteasome-specific inhibitor—as highly protective during severe heart disease. Represented by reduced heart infiltration of monocytes/macrophages and diminished organ damage, ONX 0914 treatment reversed fulminant pathology. Virus-induced immune response features like overwhelming pro-inflammatory cytokine and chemokine production as well as a progressive loss of lymphocytes all being reminiscent of a sepsis-like disease course were prevented by ONX 0914. Although the viral burden was only minimally affected in highly susceptible mice, resulting maintenance of immune homeostasis improved the cardiac output, and saved animals from severe illness as well as high mortality. Altogether, this could make ONX 0914 a potent drug for the treatment of severe virus-mediated inflammation of the heart and might rank immunoproteasome inhibitors among drugs for preventing pathogen-induced immunopathology. Resembling disease course in patients pre-disposed for severe pathogen-induced cardiac pathology, A/J mice exhibit high susceptibility for virus-induced adverse immune response activation. Systemic application of the LMP7-specific immunoproteasome inhibitor ONX 0914 inversed this hereditary predisposition.
    Print ISSN: 1757-4676
    Electronic ISSN: 1757-4684
    Topics: Medicine
    Signatur Availability
    BibTip Others were also interested in ...
  • 6
    Publication Date: 2018-01-03
    Description: Many species are shifting their ranges in response to the changing climate. In cases where such shifts lead to the colonization of a new ecosystem, it is critical to establish how the shifting species itself is impacted by novel environmental and biological interactions. Anthropogenic habitats that are analogous to the historic habitat of a shifting species may play a crucial role in the ability of that species to expand or persist in suboptimal colonized ecosystems. We tested if the anthropogenic habitat of docks, a likely mangrove analog, provides improved conditions for the range-shifting mangrove tree crab Aratus pisonii within the colonized suboptimal salt marsh ecosystem. To test if docks provided an improved habitat, we compared the impact of the salt marsh and dock habitats on ecological and life history traits that influence the ability of this species to persist and expand into the salt marsh and compared these back to baselines in the historic mangrove ecosystem. Specifically, we examined behavior, physiology, foraging, and the thermal conditions of A. pisonii in each habitat. We found that docks provide a more favorable thermal and foraging habitat than the surrounding salt marsh, while their ability to provide conditions which improved behavior and physiology was mixed. Our study shows that anthropogenic habitats can act as analogs to historic ecosystems and enhance the habitat quality for range-shifting species in colonized suboptimal ecosystems. If the patterns that we document are general across systems, then anthropogenic habitats may play an important facilitative role in the range shifts of species with continued climate change. Many species are shifting their ranges in response to the changing climate, and in cases where such shifts lead to the colonization of a new ecosystem, it is critical to establish how the shifting species itself is impacted by novel environmental and biological interactions. We tested if the anthropogenic analogous habitat of docks provides improved conditions for the range-shifting mangrove tree crab Aratus pisonii within the suboptimal colonized salt marsh ecosystem. We found that docks provide a more favorable thermal and foraging habitat than the surrounding salt marsh, while their ability to provide improved behavioral and physiological conditions was mixed.
    Electronic ISSN: 2045-7758
    Topics: Biology
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 7
    Publication Date: 2018-01-03
    Description: Many clinical laboratories now sequence the tumors from advanced cancer patients to identify oncogenic drivers and guide targeted therapies and clinical trials. One limitation of tumor sequencing is that it cannot distinguish between tumor-specific somatic (acquired) mutations and patients’ germline (constitutional) variants. To definitively identify somatic variants, some clinical labs sequence both a normal sample from a patient alongside their tumor to subtract the germline variants from the somatic variants. Having a paired normal sample also allows for the identification of secondary germline mutations in cancer patients who may not meet the current clinical guidelines for genetic testing of cancer predisposition syndromes. Such simultaneous detection of somatic alterations and germline mutations during tumor-normal sequencing can guide therapeutic decision making for cancer patients and the identification and screening of at-risk family members. Here, we review the clinical workflow, advantages and disadvantages, and clinical utility of tumor-normal sequencing in management of cancer patients.
    Print ISSN: 0022-3417
    Electronic ISSN: 1096-9896
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 8
    Publication Date: 2018-01-03
    Description: ABSTRACT Altered mRNA translational control is emerging as a critical factor in cancer development and progression. Targeting specific elements of the translational machinery, such as mTORC1 or eIF4E, is emerging as a new strategy for innovative cancer therapy. While translation of most mRNAs takes place through cap-dependent mechanisms, a sub-population of cellular mRNA species, particularly stress-inducible mRNAs with highly structured 5'-UTR regions, are primarily translated through cap-independent mechanisms. Intriguingly, many of these mRNAs encode proteins that are involved in tumour cell adaptation to microenvironmental stress, and thus linked to aggressive behaviour including tumour invasion and metastasis. This necessitates a rigorous search for links between microenvironmental stress and aggressive tumour phenotypes. Under stress, cells block global protein synthesis to preserve energy while maintaining selective synthesis of proteins that support cell survival. One highly conserved mechanism to regulate protein synthesis under cell stress is to sequester mRNAs into cytosolic aggregates called stress granules (SGs), where their translation is silenced. SGs confer survival advantages and chemotherapeutic resistance to tumour cells under stress. Recently, it has been shown that genetically blocking SG formation dramatically reduces tumour invasive and metastatic capacity in vivo . Therefore targeting SG formation might represent a potential treatment strategy to block cancer metastasis. Here we present the critical link between selective mRNA translation, stress adaptation, SGs and tumour progression. Further, we also explain how deciphering so-called selective mRNA translation occurs under cell stress holds great promise for the identification of new targets in the treatment of cancer.
    Print ISSN: 0022-3417
    Electronic ISSN: 1096-9896
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 9
    Publication Date: 2018-01-03
    Description: Background The use of MRI-tractography to explore the human neuroretina is yet to be reported. Track-weighted imaging (TWI) was recently introduced as a qualitative tractography-based method with high anatomical contrast. Purpose To explore the human retina in healthy volunteers and patients with anterior ischemic optic neuropathy (AION) using TWI reconstructions. Study Type Prospective. Population Twenty AION patients compared with 20 healthy volunteers. Field Strength/Sequence 3.0T MRI diffusion-weighted imaging (DWI) with b-value of 1000 s/mm 2 and 60 diffusion-weighting noncollinear directions. Assessment We performed constrained spherical deconvolution from the diffusion-weighted signal and volumetric tractography method, whereby 10 million streamlines are initiated from seed points randomly distributed throughout the orbital area. We then reconstructed TWI maps with isotropic voxel size of 300 μm. Statistical Tests We tested the effect of the number of diffusion-weighting directions, ocular laterality, and ocular dominance on healthy retinal fascicles distribution. We then performed factorial analysis of variance to test the effects of the presence/absence of the fascicles on the visual field defect in patients. Results In healthy volunteers, we found more temporal fascicle in right eyes ( P = 0.001), more superior fascicles in dominant eyes ( P = 0.014), and fewer fascicles with tractography maps based on 30 directions than those based on 45 directions ( P = 9 × 10 −8 ) and 60 directions ( P = 6 × 10 −7 ). Eight out of 20 AION patients presented with complete absence of neuroretinal fascicle, side of the disease, which was correlated with visual field mean deviation at the 6-month visit [F (1,17) = 6.97, P = 0.016]. Seven patients presented with a temporal fascicle in the injured eye; this fascicle presence was linked to visual field mean deviation at the 6-month visit [F (1,17) = 8.43, P = 0.009]. Data Conclusion In AION patients, the presence of the temporal neuroretinal fascicle in the affected eye provides an objective outcome radiological sign correlated with visual performance. Level of Evidence : 2 Technical Efficacy : Stage 2 J. Magn. Reson. Imaging 2018.
    Print ISSN: 1053-1807
    Electronic ISSN: 1522-2586
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 10
    Publication Date: 2018-01-03
    Description: Precise quantification of extracellular glutamate concentrations upon neuronal activation is crucial for the understanding of brain function and neurological disorders. While optogenetics is an outstanding method for the correlation between distinct neurons and their role in circuitry and behavior, the electrochemically inactive nature of glutamate has proven challenging for recording upon optogenetic stimulations. This difficulty is due to the necessity for using enzyme-coated microelectrodes and the risk for light-induced artifacts. In this study, we establish a method for the combination of in vivo optogenetic stimulation with selective measurement of glutamate concentrations using enzyme-coated multielectrode arrays and amperometry. The glutamatergic subthalamic nucleus (STN), which is the main electrode target site in deep brain stimulation treatment of advanced Parkinson′s disease, has recently proven opotogenetically targetable in Pitx2-Cre-transgenic mice and was here used as model system. Upon stereotactic injection of viral Channelrhodopsin2-eYFP constructs into the STN, amperometric recordings were performed at a range of optogenetic stimulation frequencies in the globus pallidus, the main STN target area, in anaesthetized mice. Accurate quantification was enabled through a multi-step analysis approach based on self-referencing microelectrodes and repetition of the experimental protocol at two holding potentials, which allowed for the identification, isolation and removal of photoelectric and photoelectrochemical artifacts. This study advances the field of in vivo glutamate detection with combined optogenetics and amperometric recordings by providing a validated analysis framework for application in a wide variety of glutamate-based approaches in neuroscience. This article is protected by copyright. All rights reserved.
    Print ISSN: 0022-3042
    Electronic ISSN: 1471-4159
    Topics: Medicine
    Signatur Availability
    BibTip Others were also interested in ...
  • 11
    Publication Date: 2018-01-03
    Description: Background With the disappointing outcomes of clinical trials on patients with Alzheimer's disease or mild cognitive impairment (MCI), there is increasing attention to understanding cognitive decline in normal elderly individuals, with the goal of identifying subjects who are most susceptible to imminent cognitive impairment. Purpose/Hypothesis To evaluate the potential of cerebral blood flow (CBF) as a biomarker by investigating the relationship between CBF at baseline and cognition at follow-up. Study Type Prospective longitudinal study with a 4-year time interval. Population 309 healthy subjects aged 20–89 years old. Field Strength/Sequence 3T pseudo-continuous-arterial-spin-labeling MRI. Assessment CBF at baseline and cognitive assessment at both baseline and follow-up. Statistical Tests Linear regression analyses with age, systolic blood pressure, physical activity, and baseline cognition as covariates. Results Linear regression analyses revealed that whole-brain CBF at baseline was predictive of general fluid cognition at follow-up. This effect was observed in the older group (age ≥54 years, β = 0.221, P  = 0.004), but not in younger or entire sample (β = 0.018, P  = 0.867 and β = 0.089, P  = 0.098, respectively). Among major brain lobes, frontal CBF had the highest sensitivity in predicting future cognition, with a significant effect observed for fluid cognition (β = 0.244 P  = 0.001), episodic memory (β = 0.294, P  = 0.001), and reasoning (β = 0.186, P  = 0.027). These associations remained significant after accounting for baseline cognition. Voxelwise analysis revealed that medial frontal cortex and anterior cingulate cortex, part of the default mode network (DMN), are among the most important regions in predicting fluid cognition. Data Conclusion In a healthy aging cohort, CBF can predict general cognitive ability as well as specific domains of cognitive function. Level of Evidence : 1 Technical Efficacy : Stage 3 J. Magn. Reson. Imaging 2018.
    Print ISSN: 1053-1807
    Electronic ISSN: 1522-2586
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 12
    Publication Date: 2018-01-04
    Description: Membranes assembled from two-dimensional (2D) layered materials have shown potential use in water purification. Recently, a 2D graphitic carbon nitride (g-C 3 N 4 ) nanosheets membrane exhibit considerable separation performance in water purification. In this study, to further improve this water separation performance, polyacrylic acid (PAA) was introduced to tune the nanochannels formed between the g-C 3 N 4 nanosheets. The fabricated g-C 3 N 4 -PAA hybrid membranes possessed higher water flux without sacrificing much rejection rate compared with that of the g-C 3 N 4 membrane; however noticeable fouling was observed upon addition of the PAA into the membrane composite structure. In addition, the effect of PAA on the morphology, surface hydrophilicity, separation performance, and antifouling properties of the g-C 3 N 4 membrane were examined in detail. Overall, incorporating PAA into the g-C 3 N 4 nanosheets membrane was an effective and convenient method to improve the water separation performance, which could promote the application of the 2D g-C 3 N 4 nanosheets membrane in practical ultrafiltration processes. This article is protected by copyright. All rights reserved.
    Print ISSN: 0001-1541
    Electronic ISSN: 1547-5905
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Signatur Availability
    BibTip Others were also interested in ...
  • 13
    facet.materialart.
    facet.materialart.
    Wiley-Blackwell
    Publication Date: 2018-01-04
    Description: Cover illustration. Li-LSX zeolite is the sorbent of choice for air separation via pressure swing adsorption (PSA). Due to the rapidly rising Li cost, it is desirable to minimize Li use. Li cations occupy Sites I' and II (SI' and SII) preferentially, and only cations on SIII are used for adsorption. Mixed LiCa-LSX with only a few %Li show better PSA performance compared to Ca-LSX and only slightly lower performance than pure Li-LSX. Image edited by Franklin Epiepang, University of Michigan. 10.1002/aic.16032
    Print ISSN: 0001-1541
    Electronic ISSN: 1547-5905
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Signatur Availability
    BibTip Others were also interested in ...
  • 14
    Publication Date: 2018-01-04
    Description: Objectives The primary aim of this study was to validate the Oral Disease Severity Score (ODSS) for the assessment of oral involvement in pemphigus vulgaris (PV). A secondary aim was to compare the inter – intra- observer variability and ease of use with the Physician's Global Assessment (PGA) and the oral scoring methods used in Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) and the Pemphigus Disease Area Index (PDAI). Methods 15 patients with mild to moderately severe oral PV were scored for disease severity by 10 oral medicine clinicians using the ODSS, PGA and the oral sections of ABSIS and PDAI. Two clinicians re-scored all patients after a minimum two-hour interval. Results Inter-observer reliability was assessed using an intra-class correlation coefficient (ICC). For the ODSS total score the ICC was 0.83, PDAI (oral total activity) 0.79 ABSIS (oral total) 0.71 and PGA was 0.7. Intra-observer agreement between initial scoring and re-scoring of the same subject by two clinicians demonstrated an ICC for each of 0.97 and 0.96 for ODSS total score; 0.99 and 0.82 for the PDAI oral activity; 0.86 and 0.45 for the ABSIS total and 0.99 and 0.64 for the PGA. Convergent validity was good with a correlation coefficient of greater than 0.5 (p〈0.0001). The mean time (SD) (seconds) taken to complete each scoring method was: ODSS 76±37; PDAI 117±16; ABSIS 75±19. Conclusion This study has validated the ODSS for the assessment of oral PV. It has shown superior inter- and intra-observer reliability to PDAI, ABSIS and PGA and is quick to perform. This article is protected by copyright. All rights reserved.
    Print ISSN: 0007-0963
    Electronic ISSN: 1365-2133
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 15
    Publication Date: 2018-01-04
    Description: BACKGROUND Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome caused by mutations in the tumor-suppressor gene TP53 . Osteosarcoma is a sentinel cancer in LFS. Prior studies using Sanger sequencing platforms have demonstrated that 3% of individuals with osteosarcoma harbor a mutation in TP53 . New data from next-generation sequencing have demonstrated that 3.8% of patients with osteosarcoma have a known pathogenic variant, and an additional 5.7% carry exonic variants of unknown significance in TP53 . METHODS Pediatric oncologists were e-mailed an anonymous 18-question survey assessing their willingness to offer TP53 germline testing to a child with osteosarcoma with or without a family history, and they were evaluated for changes in their choices with the prior data and the new data. RESULTS One hundred seventy-seven pediatric oncologists (22%) responded to the survey. Respondents were more likely to offer TP53 testing to a patient with a positive family history (77.4% vs 12.4%; P 〈 .0001). Significantly more providers responded that they would offer TP53 testing once they were provided with the new data (25.4% vs 12.4%; P = .0038). The proportion of providers who responded that they were unsure increased significantly when they were presented with the new data (25.4% vs 10.2%; P = .0002). Potential implications for other family members and the possibility that surveillance imaging would detect new malignancies at an earlier stage were important factors influencing a provider's decision to offer TP53 testing. CONCLUSIONS Recent data increase the proportion of providers willing to offer testing, and this suggests concern on the part of pediatric oncologists that variants of unknown significance may be disease-defining in rare cancers. Cancer 2018 . © 2018 American Cancer Society .
    Print ISSN: 0008-543X
    Electronic ISSN: 1097-0142
    Topics: Biology , Medicine
    Published by Wiley-Blackwell on behalf of The American Cancer Society.
    Signatur Availability
    BibTip Others were also interested in ...
  • 16
    Publication Date: 2018-01-04
    Description: The transport phase of the animal-mediated plant dispersal process is critical to dispersal effectiveness as it determines the spatial distribution of the diaspores released and their chance for further recruitment. Assessing this specific phase of the dispersal process generally requires combining diaspore retention times with the associated distances covered. Here, we specifically tested the effect of grooming behavior, interindividual contacts and ungulate fur on diaspore retention times and associated dispersal distances for the hooked diaspores of Xanthium strumarium L. experimentally attached to tamed individuals of three ungulate species. We used a comparative approach based on differing fur quality on different body zones of these three ungulates. During 6-hr sessions, we monitored for grooming and social interactions that may induce intended or inadvertent diaspore detachment. Additionally, we proposed innovative approaches to directly assessing diaspore dispersal distances by red deer in situ. Fat-tailed functions fitted diaspore retention time, highlighting the potential for long-distance dispersal events. The longer the hair, the higher the retention capacity of diaspores in the animal's fur. As predicted, donkey retained diaspores longer than red deer and dwarf goat; and we also confirmed that diaspores attached to the short hair of the head fell off more quickly than did those on the other body zones. Dwarf goat groomed more often than both red deer and donkey, but also when it carried diaspores. Up to 14% of the diaspores detached from animal fur after specific grooming behavior. We observed, in controlled conditions, for the first time and for each ungulate species, interindividual transfers of diaspores, representing 5% of the diaspores attached to animals’ fur. Our results militate for incorporating animal behavior into plant dispersal modeling approaches. We present important methodological updates stressing the potential for long-distance animal-mediated diaspore dispersal events using short monitoring sessions and a trait-based cross-comparative approach. We highlight the interest of coupling diaspore fate monitoring with behavioral census. This helped us describing for the first time unsuspected diaspore transfers among conspecifics.
    Electronic ISSN: 2045-7758
    Topics: Biology
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 17
    Publication Date: 2018-01-04
    Description: Aims Interobserver agreement for dysplasia in Barrett's oesophagus (BO) is low and guidelines advise expert review of dysplastic cases. We assessed the added value of p53 immunohistochemistry (IHC) on the homogeneity within a group of dedicated gastro-intestinal (GI) pathologists. Methods and results Sixty single hematoxylin & eosin (HE) slide referral BO cases (20 low-grade dysplasia (LGD); 20 high-grade dysplasia (HGD) and 20 non-dysplastic BO (NDBO) reference cases) were digitalised and independently assessed twice in a random order by 10 dedicated GI pathologists. After a ‘wash-out’ period, cases were re-assessed with the addition of a corresponding p53 IHC slide. Outcomes were 1) proportion of ‘indefinite for dysplasia’ (IND) diagnoses, 2) interobserver agreement and 3) diagnostic accuracy compared to a consensus ‘gold standard’ diagnosis defined at an earlier stage by 5 core expert BO pathologists after their assessment of this case set. Addition of p53-IHC decreased the mean proportion of IND diagnoses from 10/60 to 8/60 (p=0.071). Mean interobserver agreement increased significantly from 0.45 to 0.57 (p=0.0021). The mean diagnostic accuracy increased significantly from 72% to 82% (p=0.0072) after addition of p53 IHC. Conclusion Addition of p53-IHC significantly improves the histological assessment of BE biopsies, even within a group of dedicated GI-pathologists. It decreases the proportion of IND diagnoses and increases interobserver agreement and diagnostic accuracy. This justifies the use of accessory p53 IHC within our upcoming national digital review panel for BO biopsy cases. This article is protected by copyright. All rights reserved.
    Print ISSN: 0309-0167
    Electronic ISSN: 1365-2559
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 18
    Publication Date: 2018-01-04
    Description: Current treatment options for human stroke are limited mainly to the modestly effective infusion of tissue plasminogen activator (tPA), with additional improvement of functional independence and higher rates of angiographic revascularization observed after mechanical thrombectomy. However, new therapeutic strategies that address post-stroke immune-mediated inflammatory responses are urgently needed. Recent studies in experimental stroke have firmly implicated immune mechanisms in the propagation and partial resolution of CNS damage after the ischemic event. A new-found anti-inflammatory role for regulatory B cells (Breg) in autoimmune diseases sparked interest in these cells as potential immunomodulators in stroke. Subsequent studies identified IL-10 as a common regulatory cytokine among all five of the currently recognized Breg cell subsets, several of which can be found in the affected brain hemisphere after induction of experimental stroke in mice. Transfer of enriched Breg cell subpopulations into both B-cell depleted and wild-type mice confirmed their potent immunosuppressive activities in vivo, including recruitment and potentiation of regulatory T cells. Moreover, Breg cell therapy strongly reduced stroke volumes and treatment outcomes in ischemic mice even when administered 24 hours after induction of experimental stroke, a treatment window far exceeding that of tPA. These striking results suggest that transfer of enriched Breg cell populations could have therapeutic value in human stroke, although considerable clinical challenges remain. This article is protected by copyright. All rights reserved.
    Print ISSN: 0019-2805
    Electronic ISSN: 1365-2567
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 19
    Publication Date: 2018-01-04
    Description: Background Lung perfusion MRI after i.v. gadolinium (Gd) contrast administration is commonly based on spoiled gradient-echo acquisitions, such as volume-interpolated breath-hold examinations (VIBE), suffering from low signal-to-noise in the parenchyma. Purpose To investigate the lung signal enhancement ratio (SER) with ultra-fast steady-state free precession (ufSSFP) after Gd-administration. Study Type Retrospective. Subjects Ten subjects with healthy lungs; nine patients with pulmonary diseases (chronic obstructive pulmonary disease [COPD], lung cancer, pulmonary fibrosis, lung contusion). Field Strength/Sequence VIBE and ufSSFP imaging of the chest was performed at 1.5T before and 3 minutes after i.v. gadobenate dimeglumine. Assessment A workflow including deformable image registration and median filtering was used to compute 3D SER maps. SER was analyzed in the lung, blood pool, liver, muscles, and fat. The artifacts were assessed by a radiologist. In the COPD patients, ufSSFP-SER was compared to 99m Tc-MAA-SPECT/CT by visual scoring of lung enhancement deficits. Statistical Tests Mean signal, standard deviation (SD), intersubject SD, and coefficient of variation (CV) were calculated for SER. Statistical significance of differences in signal and artifacts were determined using Wilcoxon signed-rank paired test. Intermodality agreement between ufSSFP-SER and SPECT/CT was calculated by Cohen's kappa (κ q ). Results In healthy lungs, ufSSFP-SER (99% ± 23%, mean ± pooled intrasubject SD, CV = 23%) was significantly higher ( P  〈 10 −3 ) and more homogeneous ( P  〈 10 −3 ) than VIBE (47% ± 26%, CV = 57%). UfSSFP-SER was significantly higher ( P  〈 10 −3 ) for the lungs (99% ± 9%, mean ± intersubject SD) than for the blood (81% ± 7%) and other tissues (liver 33% ± 8%, muscle 26% ± 5%, fat 2% ± 1%). In the lung ufSSFP-SER exhibits homogeneity on iso-gravitational planes, and an anterior–posterior gradient. In COPD patients, ufSSFP-SER was reduced and less homogeneous compared to the control group (73% ± 33%, mean ± pooled intrasubject SD, CV = 42%). ufSSFP-SER had moderate intermodality agreement with SPECT/CT (κ q  = 0.64). Data Conclusion UfSSFP-SER of the lung is a rapid and simple method. Our preliminary data show plausible results in different pulmonary diseases, motivating further evaluation in larger cohorts. Level of Evidence : 2 Technical Efficacy : Stage 2 J. Magn. Reson. Imaging 2018.
    Print ISSN: 1053-1807
    Electronic ISSN: 1522-2586
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 20
    Publication Date: 2018-01-04
    Description: Purpose Accurate reconstruction of myocardial T 1 maps from a series of T 1 -weighted images consists of cardiac motions induced from breathing and diaphragmatic drifts. We propose and evaluate a new framework based on active shape models to correct for motion in myocardial T 1 maps. Methods Multiple appearance models were built at different inversion time intervals to model the blood-myocardium contrast and brightness changes during the longitudinal relaxation. Myocardial inner and outer borders were automatically segmented using the built models, and the extracted contours were used to register the T 1 -weighted images. Data acquired from 210 patients using a free-breathing acquisition protocol were used to train and evaluate the proposed framework. Two independent readers evaluated the quality of the T 1 maps before and after correction using a four-point score. The mean absolute distance and Dice index were used to validate the registration process. Results The testing data set from 180 patients at 5 short axial slices showed a significant decrease of mean absolute distance (from 3.3 ± 1.6 to 2.3 ± 0.8 mm, P  〈 0.001) and increase of Dice (from 0.89 ± 0.08 to 0.94 ± 0.4%, P  〈 0.001) before and after correction, respectively. The T 1 map quality improved in 70 ± 0.3% of the motion-affected maps after correction. Motion-corrupted segments of the myocardium reduced from 21.8 to 8.5% ( P  〈 0.001) after correction. Conclusion The proposed method for nonrigid registration of T 1 -weighted images allows T 1 measurements in more myocardial segments by reducing motion-induced T 1 estimation errors in myocardial segments. Magn Reson Med, 2018. © 2018 International Society for Magnetic Resonance in Medicine.
    Print ISSN: 0740-3194
    Electronic ISSN: 1522-2594
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 21
    Publication Date: 2018-01-04
    Description: Purpose To develop an accurate T 1 measurement method for short T 2 tissues using a combination of a 3-dimensional ultrashort echo time cones actual flip angle imaging technique and a variable repetition time technique (3D UTE-Cones AFI-VTR) on a clinical 3T scanner. Methods First, the longitudinal magnetization mapping function of the excitation pulse was obtained with the 3D UTE-Cones AFI method, which provided information about excitation efficiency and B 1 inhomogeneity. Then, the derived mapping function was substituted into the VTR fitting to generate accurate T 1 maps. Numerical simulation and phantom studies were carried out to compare the AFI-VTR method with a B 1 -uncorrected VTR method, a B 1 -uncorrected variable flip angle (VFA) method, and a B 1 -corrected VFA method. Finally, the 3D UTE-Cones AFI-VTR method was applied to bovine bone samples ( N  = 6) and healthy volunteers ( N  = 3) to quantify the T 1 of cortical bone. Results Numerical simulation and phantom studies showed that the 3D UTE-Cones AFI-VTR technique provides more accurate measurement of the T 1 of short T 2 tissues than the B 1 -uncorrected VTR and VFA methods or the B 1 -corrected VFA method. The proposed 3D UTE-Cones AFI-VTR method showed a mean T 1 of 240 ± 25 ms for bovine cortical bone and 218 ± 10 ms for the tibial midshaft of human volunteers, respectively, at 3 T. Conclusion The 3D UTE-Cones AFI-VTR method can provide accurate T 1 measurements of short T 2 tissues such as cortical bone. Magn Reson Med, 2018. © 2018 International Society for Magnetic Resonance in Medicine.
    Print ISSN: 0740-3194
    Electronic ISSN: 1522-2594
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 22
    Publication Date: 2018-01-05
    Description: Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths that will occur in the United States and compiles the most recent data on cancer incidence, mortality, and survival. Incidence data, available through 2014, were collected by the Surveillance, Epidemiology, and End Results Program; the National Program of Cancer Registries; and the North American Association of Central Cancer Registries. Mortality data, available through 2015, were collected by the National Center for Health Statistics. In 2018, 1,735,350 new cancer cases and 609,640 cancer deaths are projected to occur in the United States. Over the past decade of data, the cancer incidence rate (2005-2014) was stable in women and declined by approximately 2% annually in men, while the cancer death rate (2006-2015) declined by about 1.5% annually in both men and women. The combined cancer death rate dropped continuously from 1991 to 2015 by a total of 26%, translating to approximately 2,378,600 fewer cancer deaths than would have been expected if death rates had remained at their peak. Of the 10 leading causes of death, only cancer declined from 2014 to 2015. In 2015, the cancer death rate was 14% higher in non-Hispanic blacks (NHBs) than non-Hispanic whites (NHWs) overall (death rate ratio [DRR], 1.14; 95% confidence interval [95% CI], 1.13-1.15), but the racial disparity was much larger for individuals aged 〈65 years (DRR, 1.31; 95% CI, 1.29-1.32) compared with those aged ≥65 years (DRR, 1.07; 95% CI, 1.06-1.09) and varied substantially by state. For example, the cancer death rate was lower in NHBs than NHWs in Massachusetts for all ages and in New York for individuals aged ≥65 years, whereas for those aged 〈65 years, it was 3 times higher in NHBs in the District of Columbia (DRR, 2.89; 95% CI, 2.16-3.91) and about 50% higher in Wisconsin (DRR, 1.78; 95% CI, 1.56-2.02), Kansas (DRR, 1.51; 95% CI, 1.25-1.81), Louisiana (DRR, 1.49; 95% CI, 1.38-1.60), Illinois (DRR, 1.48; 95% CI, 1.39-1.57), and California (DRR, 1.45; 95% CI, 1.38-1.54). Larger racial inequalities in young and middle-aged adults probably partly reflect less access to high-quality health care. CA Cancer J Clin 2018 . © 2018 American Cancer Society .
    Print ISSN: 0007-9235
    Electronic ISSN: 1542-4863
    Topics: Medicine
    Published by Wiley-Blackwell on behalf of American Cancer Society.
    Signatur Availability
    BibTip Others were also interested in ...
  • 23
    Publication Date: 2018-01-05
    Description: The overall objective of the guideline is to provide up-to-date, evidence-based recommendations for the management of lichen sclerosus (LS) in adults (18+ years), children (0-12 years) and young people (13-17 years). The document aims to. offer an appraisal of all relevant literature up to July 2017, focusing on any key developments. address important, practical clinical questions relating to the primary guideline objective. provide guideline recommendations and if appropriate research recommendations. The guideline is presented as a detailed review with highlighted recommendations for practical use in primary care and in secondary care clinics, in addition to an updated Patient Information Leaflet (PIL; available on the BAD website, http://www.bad.org.uk/for-the-public/patient-information-leaflets ). This article is protected by copyright. All rights reserved.
    Print ISSN: 0007-0963
    Electronic ISSN: 1365-2133
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 24
    Publication Date: 2018-01-04
    Description: A challenge in developing personalized cancer immunotherapies is the prediction of putative cancer-specific antigens. Currently, predictive algorithms are used to infer binding of peptides to human leukocyte antigen (HLA) heterodimers to aid in the selection of putative epitope targets. One drawback of current epitope prediction algorithms is that they are trained on datasets containing biochemical HLA-peptide binding data that may not completely capture the rules associated with endogenous processing and presentation. The field of mass spectrometry has made great improvements in instrumentation speed and sensitivity, chromatographic resolution, and proteogenomic database search strategies to facilitate the identification of HLA-ligands from a variety of cell types and tumor tissues. As such, these advances have enabled mass spectrometry profiling of HLA-binding peptides to be a tractable, orthogonal approach to lower throughput biochemical assays for generating comprehensive datasets to train epitope prediction algorithms. In this review, we will highlight the progress made in the field of HLA-ligand profiling enabled by mass spectrometry and its impact on current and future epitope prediction strategies. This article is protected by copyright. All rights reserved
    Print ISSN: 1615-9853
    Electronic ISSN: 1615-9861
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 25
    Publication Date: 2018-01-04
    Description: Evolution found itself in a Catch-22 situation when selecting for the somatically derived paratopic repertoire of the humoral immune system. The B-cell BCR repertoire can only be somatically diversified from a substrate of paratopes that is encoded in the germline. In order for the cells expressing that substrate to also be a target of germline selection, their BCRs must, independently, be of selective value by being expressed in a functionally important way in each individual. A somatically derived repertoire scrambles this substrate so that its specificities are lost, making it unselectable in the germline. Consequently, evolution faced an incompatibility. Here we explore what it takes to resolve it. This article is protected by copyright. All rights reserved.
    Print ISSN: 0300-9475
    Electronic ISSN: 1365-3083
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 26
    Publication Date: 2018-01-05
    Description: MicroRNAs (miRNAs) are known regulators of various cellular processes, including pluripotency and differentiation of embryonic stem cells (ESCs). We analyzed differentiation of two ESC lines - D3 and B8, and observed significant differences in the expression of miRNAs and genes involved in pluripotency and differentiation. We also examined if transient miRNA overexpression could serve as a sufficient impulse modulating differentiation of mouse ESCs. ESCs were transfected with miRNA Mimics and differentiated in embryoid bodies and embryoid body outgrowths. miRNAs involved in differentiation of mesodermal lineages, such as miR145 and miR181, as well as miRNAs regulating myogenesis (MyomiRs) - miR1, miR133a, miR133b, and miR206 were tested. Using such approach we proved that transient overexpression of molecules selected by us modulated differentiation of mouse ESCs. Increase in miR145 levels upregulated Pax3 , Pax7 , Myod1, Myog, and MyHC2, while miR181 triggered the expression of such crucial myogenic factors as Myf5 and MyHC2 . As a result the ability of ESCs to initiate myogenic differentiation and form myotubes was enhanced. Premature expression of myomiRs had, however, an adverse effect on myogenic differentiation of ESCs. This article is protected by copyright. All rights reserved. miRNAs in ESCs differentiating in embryoid bodies (EBs) and embryoid body outgrowths (EBOs). A. NGS miRNA profiling shows significant differences between D3 and B8 ESC lines; B. Transient miRNA overexpression affects myogenic differentiation. The effect of miR145, miR181 or miR206 overexpression visualized with qPCR and immunodetection of skMyHC (C) .
    Print ISSN: 1066-5099
    Electronic ISSN: 1549-4918
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 27
    Publication Date: 2018-01-05
    Description: Human DEAD-box RNA helicase gene DDX6 was cloned from B-cell lymphoma cell line RC-K8. Previously, we reported that DDX6 acts as oncogene in several cancers such as colorectal cancer and hepatocellular carcinoma. However, the detailed mechanism of DDX6 action in carcinogenesis is largely unknown. In this study, we examined the functions of DDX6 in clinical gastric cancer (GC) samples and GC cells. DDX6 protein expression levels of cancer samples were higher than those of the adjacent normal tissues in 25 clinical GC samples (median value: 1.4 times higher). Also, the results of an RNA immunoprecipitation-assay (RIP-assay) showed that DDX6 associated with c-Myc mRNA. Moreover, enforced overexpression of DDX6 promoted both mRNA and protein expression of c-Myc in GC cells. On the other hand, the gene silencing of DDX6 induced growth suppression through down-regulation of c-Myc in GC cells grown in either 2 or 3 dimensions. Furthermore, c-Myc mRNA expression levels of cancer samples were higher than those of the adjacent normal tissues in DDX6 up-regulated-GC clinical samples. Our findings in this study suggested that DDX6 acted as oncogene in GC cells through promotion of c-Myc expression by association with the mRNA of c-Myc. This article is protected by copyright. All rights reserved
    Print ISSN: 0899-1987
    Electronic ISSN: 1098-2744
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 28
    Publication Date: 2018-01-05
    Description: Aims Cystic lesions derived from the synovial and ligamentous structures of the spine have varied histologic appearances. Not uncommonly, there is discrepancy between the clinico-radiologic diagnosis and histology. Therefore, we sought to characterize the histologic features of tissue submitted as “synovial cysts” of the spine. Methods Resected specimens of the spine labeled “synovial cysts” and “lumbar cysts” were histologically evaluated and classified based on histopathologic features. Results 75 histologic samples of spinal cysts were identified. 31 were classified as synovial cysts (definite synovial lining), 28 showed pseudocystic degeneration of the ligamentum flavum, 7 showed pseudocyst formation without evidence of synovial lining or degeneration of the ligamentum flavum, 8 showed cyst contents only or no histologic evidence of cyst wall for evaluation. Twenty-five cases (33%), especially those showing pseudocystic degeneration of the ligamentum flavum were associated with very characteristic tumor calcinosis-like calcium deposition with surrounding foreign-body giant cell reaction. Conclusion Histology of “synovial cysts” of the spine shows varied types of cysts; a large proportion are not synovial lined cysts but rather show pseudocystic degenerative changes of the ligamentum flavum often associated with very characteristic finely granular calcifications and foreign body giant cell reaction. This may have implications, not only in understanding the pathogenesis of these lesions, but also in their varied response to non-surgical interventions. This article is protected by copyright. All rights reserved.
    Print ISSN: 0309-0167
    Electronic ISSN: 1365-2559
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 29
    Publication Date: 2018-01-05
    Description: Aims Distinguishing between aggressive NK-cell leukaemia (ANKCL) and extranodal NK/T-cell lymphoma (ENKTCL) with secondary bone marrow involvement is challenging, as they are rare bone marrow NK/T-cell neoplasms and share similar features. Methods and results We studied bone marrow NK/T-cell neoplasms by classifying them into those with no extramedullary mass (group 1, 8 cases) and those with extramedullary mass (group 2, 13 cases). Both groups showed similar clinical presentations and pathological features. Fever and cytopenia were the most common clinical presentations in both groups. The neoplastic cells varied from small and relatively monotonous cells to large pleomorphic cells. In six cases (2 in group 1 and 4 in group 2), the neoplastic infiltrate was inconspicuous, consisting of ≤10% of marrow cells in the interstitium, which were hardly identified by H&E stain alone. Nearly all patients were rapidly fatal no matter the neoplastic infiltrate volume. All the patients in group 1 fulfilled the WHO 2017 diagnostic criteria of ANKCL and their survivals were significantly worse than those of the group 2 patients ( P = 0.035). In addition, group 1 patients were significantly associated with chromosome 7 abnormalities. Chromosome 6q deletion, commonly reported in ENKTCL, was seen in two of our group 2 patients, and was not observed in any of our group 1 patients. Conclusion ANKCL with no extramedullary mass should be distinguished from ENKTCL with bone marrow involvement as the former showed distinct outcome and genetic features. This article is protected by copyright. All rights reserved.
    Print ISSN: 0309-0167
    Electronic ISSN: 1365-2559
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 30
    Publication Date: 2018-01-05
    Description: Aims The present study compared treated lymphoma-associated EBV-positive mucocutaneous ulcer (EBVMCU) and methotrexate (MTX)-associated EBVMCU. Methods and results Of a series of 15 Japanese patients (11 women, 4 men; median age 74 years, range 35–84 years). 7 received MTX for autoimmune disease and 8 developed EBVMCU after treatment of malignant lymphoma (diffuse large B-cell lymphoma [n=4] without EBV association, adult T-cell leukaemia/lymphoma [n=2], angioimmunoblastic T-cell lymphoma [n=1], and follicular lymphoma [n=1]). Ulcers were observed in the oral cavity (n=11), GI tract (n=2), and skin (n=2). All were histologically characterized by a mixture of EBV-positive large B-cell proliferation and Hodgkin-Reed Sternberg-like cells on a polymorphous background. A total of 46% (6/13) had monoclonal IgH gene rearrangement, but none had clonal T-cell receptor gene rearrangement. Spontaneous regression occurred in 13/15 cases (87%); the other 2 cases (13%) achieved complete remission after treatment. In two patients in the treated lymphoma-associated subgroup, one developed multiple new ulcerative lesions on previously unaffected skin and the other had a relapse of EBVMCU in the oral cavity. No significant clinicopathological differences were found between the subgroups. Notably, none of the patients died from EBVMCU. However, the treated lymphoma-associated subgroup had lower overall survival (P=0.004) and a shorter follow-up period (P=0.003) than the MTX-associated subgroup due to death by non-associated causes. Conclusions Treated lymphoma-associated EBVMCU, an indolent and self-limited condition, must be recognized to avoid misdiagnosing it as a relapse of malignant lymphoma during treatment. This article is protected by copyright. All rights reserved.
    Print ISSN: 0309-0167
    Electronic ISSN: 1365-2559
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 31
    Publication Date: 2018-01-05
    Description: Cutaneous melanoma (CM) is considered as a steroid hormone-related malignancy. However, few studies have evaluated the roles of genetic variants encoding steroid hormone receptor genes and their related regulators (SHR-related genes) in CM-specific survival (CMSS). Here, we performed a pathway-based analysis to evaluate genetic variants of 191 SHR-related genes in 858 CMSS patients using a dataset from a genome-wide association study (GWAS) from The University of Texas MD Anderson Cancer Center (MDACC), and then validated the results in an additional dataset of 409 patients from the Harvard GWAS. Using multivariate Cox proportional hazards regression analysis, we identified three independent SNPs ( RORA rs782917 G〉A, RORA rs17204952 C〉T and DNMT1 rs7253062 G〉A) as predictors of CMSS, with a variant-allele attributed hazards ratio (HR) and 95% confidence interval of 1.62 (1.25-2.09), 1.60 (1.20-2.13) and 1.52 (1.20-1.94), respectively. Combined analysis of risk genotypes of these three SNPs revealed a decreased CMSS in a dose-response manner as the number of risk genotypes increased ( P trend  〈 0.001); however, no improvement in the prediction model was observed (area under the curve [AUC] = 79.6% to 80.8%, P = 0.656), when these risk genotypes were added to the model containing clinical variables. Our findings suggest that genetic variants of RORA and DNMT1 may be promising biomarkers for CMSS, but these results needed to be validated in future larger studies. This article is protected by copyright. All rights reserved.
    Print ISSN: 0020-7136
    Electronic ISSN: 1097-0215
    Topics: Biology , Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 32
    Publication Date: 2018-01-05
    Description: Adoptive cell transfer (ACT) is an emerging and promising cancer immunotherapy that has been improved through various approaches. Here, we described the distinctive characteristics and functions of tumor Ag-specific effector CD8 + T-cells, co-cultured with a tumor specific peptide and a stimulatory anti-OX40 antibody, before being used for ACT therapy in tumor-bearing mouse recipients. Splenic T-cells were obtained from wild-type FVB/N mice that had been injected with a HER2/neu (neu)-expressing tumor and a neu-vaccine. The cells were then incubated for seven days in vitro with a major histocompatibility complex (MHC) class I peptide derived from neu, in the presence or absence of an agonistic anti-OX40 monoclonal antibody, before CD8 + T cells were isolated for use in ACT therapy. The proliferative ability of OX40-driven tumor Ag-specific effector CD8 + T-cells in vitro was less than that of non-OX40-driven tumor Ag-specific effector CD8 + T-cells, but they expressed significantly more early T-cell differentiation markers, such as CD27, CD62L, and CCR7, and significantly higher levels of Bcl-2, an anti-apoptotic protein. These OX40-driven tumor Ag-specific effector CD8 + T-cells, when transferred into tumor-bearing recipients, demonstrated potent proliferation capability and successfully eradicated the established tumor. In addition, these cells exhibited long-term antitumor function, and appeared to be established as memory T-cells. Our findings suggest a possible in vitro approach for improving the efficacy of ACT, which is simple, requires only a small amount of modulator, and can potentially avoid several toxicities associated with co-stimulation in vivo . This article is protected by copyright. All rights reserved.
    Print ISSN: 0020-7136
    Electronic ISSN: 1097-0215
    Topics: Biology , Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 33
    Publication Date: 2018-01-05
    Description: Previous case-control studies have suggested that atopic allergic conditions (AACs) are inversely associated with pancreatic cancer, but this relationship has not been supported in many prospective settings. In this study, we investigated the influence of AACs (asthma, hay fever, or allergy) and the treatment of these conditions on pancreatic cancer risk among participants of the Multiethnic Cohort Study (MEC). AACs and antihistamine use were assessed via a baseline questionnaire when participants joined the MEC in 1993-1996. Risk ratios (RRs) and 95% confidence intervals (CIs) for pancreatic cancer incidence by AACs and antihistamines were calculated using Cox regression, adjusting for age, sex, ethnicity, education, smoking status, family history of pancreatic cancer, body mass index, diabetes, and alcohol intake. We further evaluated associations among subgroups defined by age, sex, ethnicity, follow-up time and known pancreatic cancer risk factors. During an average 16-year follow-up, 1,455 incident cases of pancreatic cancer were identified among 187,226 white, African American, Latino, Japanese American and Native Hawaiian men and women. AACs (RR 1.00, 95% CI 0.88-1.12) and antihistamines (RR 0.92, 95% CI 0.78-1.07) were not clearly associated with pancreatic cancer incidence. While these associations were also null for most subgroups, we did observe protective associations of AACs (RR 0.74, 95% CI 0.56-0.98) and antihistamines (RR 0.66, 95% CI 0.45-0.96) among the oldest participants (70+). Our results, in agreement with past prospective studies, suggest that AACs are not associated with pancreatic cancer in general, but the observed protective associations among the oldest age group may warrant future investigation. This article is protected by copyright. All rights reserved.
    Print ISSN: 0020-7136
    Electronic ISSN: 1097-0215
    Topics: Biology , Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 34
    Publication Date: 2018-01-05
    Description: HPV-positive head and neck squamous cell carcinoma (HNSCC) is increasingly frequent. Management is particularly debated in the case of post-surgical high-risk features, i.e., positive surgical margins and extracapsular spread (ECS). In this increasingly complex emerging framework of HNSCC treatment, representative pre-clinical models are needed to support future clinical trials and advances in personalized medicine. Here, we present an immunocompetent mouse model based on the implantation of mouse tonsil epithelial HPV16-E6/E7-expressing cancer cells into the submental region of the floor-of-the-mouth. Primary tumors were found to replicate the patterns of human HNSCC local invasion and lymphatic dissemination. To study disease progression after surgery, tumors were removed with residual disease. Surgical resection of tumors was followed by a high rate of local recurrences (〉90%) within the first 2 to 3 weeks. While only 50% of mice had lymph node metastases (LNM) at time of primary tumor excision, all mice with recurrent tumors showed evidence of LNM. To study the consecutive steps of LNM progression and distant metastasis development, LNs from tumor-bearing mice were transplanted into naïve recipient mice. Using this approach, transplanted LNs were found to recapitulate all stages and relevant histological features of regional metastasis progression, including ECS and metastatic spread to the lungs. Altogether, we have developed an immunocompetent HPV-positive HNSCC mouse model of post-surgical local recurrence and regional and distant metastasis progression suitable for pre-clinical studies. This article is protected by copyright. All rights reserved.
    Print ISSN: 0020-7136
    Electronic ISSN: 1097-0215
    Topics: Biology , Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 35
    facet.materialart.
    facet.materialart.
    Wiley-Blackwell
    Publication Date: 2018-01-05
    Description: Recent next-generation-sequencing studies demonstrate that multiple pathways are often deregulated in advanced and metastatic prostate cancer (PC). In a recent issue of The Journal of Pathology , an elegant study by Jefferies et al used in vivo modelling to demonstrate how activation of the PI3K, WNT and MAPK pathway converges on mTORC1 signalling to drive aggressive disease. The study also highlights that approaches to target advanced PC require intelligent combination of agents to target single/multiple signalling pathways in combination with androgen receptor (AR) blockade.
    Print ISSN: 0022-3417
    Electronic ISSN: 1096-9896
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 36
    Publication Date: 2018-01-05
    Description: Cocaine- and amphetamine-regulated transcript (CART) peptide is a widely distributed neurotransmitter that attenuates cocaine-induced locomotor activity when injected into the nucleus accumbens (NAc). Our previous work first confirmed that the inhibitory mechanism of the CART peptide on cocaine-induced locomotor activity is related to a reduction in cocaine-enhanced phosphorylated Ca 2+ /calmodulin-dependent protein kinaseIIα (pCaMKIIα) and the enhancement of cocaine-induced D3R function. The present study investigated whether CART peptide inhibited cocaine-induced locomotor activity via inhibition of interactions between pCaMKIIα and the D3 dopamine receptor (D3R). We demonstrated that lentivirus-mediated gene transfer transiently increased pCaMKIIα expression, which peaked at 10 days after microinjection into the rat NAc shell, and induced a significant increase in Ca 2+ influx along with greater behavioral sensitivity in the open field test after intraperitoneal injections of cocaine (15 mg/kg). However, western blot analysis and coimmunoprecipitation demonstrated that CART peptide treatment in lentivirus-transfected CaMKIIα-overexpressing NAc rat tissues or cells prior to cocaine administration inhibited the cocaine-induced Ca 2+ influx and attenuated the cocaine-increased pCaMKIIα expression in lentivirus-transfected CaMKIIα-overexpressing cells. CART peptide decreased the cocaine-enhanced phosphorylated cAMP response element binding protein (pCREB) expression via inhibition of the pCaMKIIα-D3R interaction, which may account for the prolonged locomotor sensitization induced by repeated cocaine treatment in lentivirus-transfected CaMKIIα-overexpressing cells. These results provide strong evidence for the inhibitory modulation of CART peptide in cocaine-induced locomotor sensitization. This article is protected by copyright. All rights reserved.
    Print ISSN: 0022-3042
    Electronic ISSN: 1471-4159
    Topics: Medicine
    Signatur Availability
    BibTip Others were also interested in ...
  • 37
    Publication Date: 2018-01-05
    Description: Statistical prediction methods typically require some form of fine-tuning of tuning parameter(s), with K -fold cross-validation as the canonical procedure. For ridge regression, there exist numerous procedures, but common for all, including cross-validation, is that one single parameter is chosen for all future predictions. We propose instead to calculate a unique tuning parameter for each individual for which we wish to predict an outcome. This generates an individualized prediction by focusing on the vector of covariates of a specific individual. The focused ridge—fridge—procedure is introduced with a 2-part contribution: First we define an oracle tuning parameter minimizing the mean squared prediction error of a specific covariate vector, and then we propose to estimate this tuning parameter by using plug-in estimates of the regression coefficients and error variance parameter. The procedure is extended to logistic ridge regression by using parametric bootstrap. For high-dimensional data, we propose to use ridge regression with cross-validation as the plug-in estimate, and simulations show that fridge gives smaller average prediction error than ridge with cross-validation for both simulated and real data. We illustrate the new concept for both linear and logistic regression models in 2 applications of personalized medicine: predicting individual risk and treatment response based on gene expression data. The method is implemented in the R package fridge .
    Print ISSN: 0277-6715
    Electronic ISSN: 1097-0258
    Topics: Mathematics , Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 38
    Publication Date: 2018-01-05
    Description: Oligodendrocyte precursor cells (OPCs) give rise to oligodendrocytes in cerebral white matter. However, the underlying mechanisms that regulate this process remain to be fully defined, especially in adult brains. Recently, it has been suggested that signaling via A-kinase anchor protein 12 (AKAP12), a scaffolding protein that associates with intracellular molecules such as protein kinase A, may be involved in Schwann cell homeostasis and peripheral myelination. Here, we asked whether AKAP12 also regulates the mechanisms of myelination in the CNS. AKAP12 knockout mice were compared against wild-type mice in a series of neurochemical and behavioral assays. Compared to wild-types, 2-month old AKAP12 knockout mice exhibited loss of myelin in white matter of the corpus callosum, along with perturbations in working memory as measured by a standard Y-maze test. Unexpectedly, very few OPCs expressed AKAP12 in the corpus callosum region. Instead, pericytes appeared to be one of the major AKAP12-expressing cells. In a cell culture model system, conditioned culture media from normal pericytes promoted in-vitro OPC maturation. However, conditioned media from AKAP12-deficient pericytes did not support the OPC function. These findings suggest that AKAP12 signaling in pericytes may be required for OPC-to-oligodendrocyte renewal to maintain the white matter homeostasis in adult brain. This article is protected by copyright. All rights reserved. In adult white matter, AKAP12 in pericytes regulates the production of growth factors, which promote oligodendrocyte differentiation for maintaining white matter homeostasis.
    Print ISSN: 1066-5099
    Electronic ISSN: 1549-4918
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 39
    Publication Date: 2018-01-05
    Description: Tendon repair is a clinical challenge because of the limited understanding on tenogenesis. The synthesis of Type I collagen (Collagen I) and other extracellular matrix (ECM) are essential for tendon differentiation and homeostasis. Current studies on tenogenesis focused mostly on the tenogenic transcriptional factors while the signaling controlling tenogenesis on translational level remains largely unknown. Here we showed that mechanistic target of rapamycin (mTOR) signaling was activated by protenogenic growth factor, transforming growth factors beta1 (TGF-β1) and insulin-like growth factor-I (IGF-1). The expression of mTOR was upregulated during tenogenesis of mesenchymal stem cells (MSCs). Moreover, mTOR was downregulated in human tendinopathy tissues and was inactivated upon statin treatment. Both inhibition and depletion of AKT or mTOR significantly reduced Type I collagen production and impaired tenogenesis of MSCs. Tendon specific-ablation of mTOR resulted in tendon defect and reduction of Collagen I. However, there is no evident downregulation of tendon associated collagens at the transcription level. Our study demonstrated that AKT-mTOR axis is a key mediator of tendon differentiation and provided a novel therapeutic target for tendinopathy and tendon injuries. This article is protected by copyright. All rights reserved. Current studies on tenogenesis have focused mostly on the tenogenic transcription factors including SCX, MKX, and EGR. These tenogenic transcription factors are upregulated by pro-tendon growth factors, such as TGF-β and IGF-1. Here we demonstrated that AKT-mTOR axis can be activated during tenogenesis.Knockout of mTOR resulted in tendon defects. Our finding strongly supports that AKT-mTOR axis serves as a novel essential node for tenogenesis.
    Print ISSN: 1066-5099
    Electronic ISSN: 1549-4918
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 40
    Publication Date: 2018-01-06
    Description: While long-term survival rates for early-stage lung cancer are high, most cases are diagnosed in later stages that can negatively impact survival rates. We aim to design a simple, single biomarker blood test for early-stage lung cancer that is robust to preclinical variables and can be readily implemented in the clinic. Whole blood was collected in PAXgene tubes from a training set of 29 patients, and a validation set of 260 patients, of which samples from 58 patients were prospectively collected in a clinical trial specifically for this study. After RNA was extracted, the expression of FPR1 and a reference gene were quantified by an automated one-step Taqman RT-PCR assay. Elevated levels of FPR1 mRNA in whole blood predicted lung cancer status with a sensitivity of 55% and a specificity of 87% on all validation specimens. The prospectively collected specimens had a significantly higher 68% sensitivity and 89% specificity. Results from patients with benign nodules were similar to healthy volunteers. No meaningful correlation was present between our test results and any clinical characteristic other than lung cancer diagnosis. FPR1 mRNA levels in whole blood can predict the presence of lung cancer. Using this as a reflex test for positive lung cancer screening computed tomography (CT) scans has the potential to increase the positive predictive value. This marker can be easily measured in an automated process utilizing off-the-shelf equipment and reagents. Further work is justified to explain the source of this biomarker. This article is protected by copyright. All rights reserved.
    Print ISSN: 0020-7136
    Electronic ISSN: 1097-0215
    Topics: Biology , Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 41
    Publication Date: 2018-01-06
    Description: Background Cerebral blood volume (CBV) mapping with a dynamic susceptibility contrast (DSC) perfusion technique has become a clinical tool in diagnosing and follow-up of brain tumors. Ferumoxytol, a long-circulating iron oxide nanoparticle, has been tested for CBV mapping, but the optimal dose has not been established. Purpose To compare ferumoxytol DSC of two different doses to standard of care gadoteridol by analyzing time–intensity curves and CBV maps in normal-appearing brain regions. Study Type Retrospective. Subjects Fifty-four patients with various brain disorders. Field Strength/Sequence 3T MRI. DSC-MRI was performed with 0.1 mmol/kg gadoteridol and 1 day later with ferumoxytol in doses of 1 or 2 mg/kg. Assessment Signal changes during first pass, relative CBV (rCBV) in normal-appearing thalamus, putamen, and globus pallidus, and contrast-to-noise ratio (CNR) of the CBV maps were compared between gadoteridol and various doses of ferumoxytol using an automated method. To subjectively assess the quality of the CBV maps, two blinded readers also assessed visual conspicuity of the putamen. Statistical Tests Linear mixed effect model was used for statistical comparison. Results Compared to gadoteridol, 1 mg/kg ferumoxytol showed no difference in CNR ( P = 0.6505), peak ΔR2*, and rCBV in the putamen ( P = 0.2669, 0.0871) or in the thalamus ( P = 0.517, 0.9787); 2 mg/kg ferumoxytol increased peak ΔR2* as well as the CNR ( P 〈 0.0001), but also mildly increased rCBV in putamen and globus pallidus ( P = 0.0005, 0.0012). Signal intensities during first pass remained highly above the noise level, with overlapping of 95% confidence intervals with noise only in 3 out of 162 tested regions. Compared to gadoteridol, the visual image quality showed mild improvement with 1 mg/kg ( P = 0.02) and marked improvement with 2 mg/kg ferumoxytol ( P 〈 0.0001). Data Conclusion 1 mg/kg ferumoxytol provides similar imaging results to standard gadoteridol for DSC-MRI, and 2 mg/kg has a benefit of increased CNR, but may also result in mildly increased rCBV values. Level of Evidence: 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018.
    Print ISSN: 1053-1807
    Electronic ISSN: 1522-2586
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 42
    Publication Date: 2018-01-07
    Description: ABSTRACT Background: Quantification of regulatory T cells is crucial in immunomonitoring in clinical trials as this cell population has been shown to be involved in a wide range of diseases, including cancers, autoimmune diseases, infections and allergies. Human regulatory T cells are defined as CD4 + CD25 + CD127 low FoxP3 + cells, and the standardization of their staining by flow cytometry is a challenge, especially in multicenter clinical trials, notably because of the intracellular location of FoxP3. Method: A flow cytometry staining procedure was settled and standardized to measure human regulatory T cells in peripheral whole blood using pre-coated dried antibodies in ready-to-use tubes. It was compared to reference methods and implemented and validated to be suitable with different cytometer platforms. Results: The standardized protocol developed with dried antibodies and reduced volumes of whole blood allows an optimal identification of regulatory T cells. Compared to classical staining procedure, it reduces the number of steps required, in a very fast and simple technique. The accuracy of the method was confirmed by a multicenter comparison with different cytometer brands. Conclusion: Our results highlight the reliability of this high-standard protocol that could become a reference method for the monitoring of regulatory T cells in clinical trials. This article is protected by copyright. All rights reserved.
    Topics: Biology , Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 43
    Publication Date: 2018-01-07
    Description: Currently published studies have implicated that microRNAs (miRNAs) including exosomes-encapsulated miRNAs play a critical role in rheumatoid arthritis (RA). Previously, we have found that exosomes-encapsulated miR-548a-3p was significantly decreased in serum samples from RA patients by miRNAs microarray analysis. However, little is known of the role of miR-548a-3p in the development and progression of RA. In this study, we aim to investigate the underlying molecular mechanisms of miR-548a-3p in RA, which will provide new insight into understanding the pathogenesis of RA and identifying novel therapeutics targets for this disease. As validated by quantitative real-time polymerase chain reaction (qRT-PCR), the expression of miR-548a-3p in serum exosomes and peripheral blood mononuclear cells (PBMCs) of RA patients (n = 76) was obviously down-regulated compared with healthy controls (n = 20). Serum exosomal miR-548a-3p was negatively associated with levels of CRP, RF and ESR in serum of patients with RA. MiR-548a-3p could inhibit the proliferation and activation of pTHP-1 cells by regulating the TLR4/NF-κB signaling pathway. Accordingly, exosomes-delivered miR-548a-3p may be a critical factor predicting the disease activity of RA. MiR-548a-3p/TLR4/NF-κB axis can serve as promising targets for RA diagnosis and treatment. This article is protected by copyright. All rights reserved
    Electronic ISSN: 0091-7419
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 44
    Publication Date: 2018-01-07
    Description: The etiology of Alzheimer's disease (AD) is egregiously comprehended, but epidemiological studies have posited that diets rich in the saturated fatty acid palmitic acid (palmitate) are a significant risk factor. The production and accumulation of Amyloid-beta peptide (Aβ) is considered the core pathological molecular event in the pathogenesis of AD. The rate limiting step in Aβ genesis from Amyloid-β precursor protein (AβPP) is catalyzed by the enzyme β-site APP cleaving enzyme 1 (BACE1), the expression and enzymatic activity of which is significantly upregulated in the AD brain. In this study, we determined the molecular mechanisms that potentially underlie the palmitate-induced up-regulation in BACE1 expression and augmented Aβ production. We demonstrate that a palmitate-enriched diet and exogenous palmitate treatment evoke an increase in BACE1 expression and activity leading to enhanced Aβ genesis in the mouse brain and SH-SY5Y-APP S we cells respectively, through the activation of the transcription factor NF-κB. Chromatin Immunoprecipitation (ChIP) assays and luciferase reporter assays revealed that palmitate enhances BACE1 expression by increasing the binding of NF-κB in the BACE1 promoter followed by an enhancement in the transactivation of the BACE1 promoter. Elucidation and delineation of upstream molecular events unveiled a critical role of the endoplasmic reticulum (ER) stress-associated transcription factor, C/EBP Homologous Protein (CHOP) in the palmitate-induced NF-κB activation, as CHOP knock-down cells and Chop -/- mice do not exhibit the same degree of NF-κB activation in response to the palmitate challenge. Our study delineates a novel CHOP-NF-κB signaling pathway that mediates palmitate-induced up-regulation of BACE1 expression and Aβ genesis. This article is protected by copyright. All rights reserved.
    Print ISSN: 0022-3042
    Electronic ISSN: 1471-4159
    Topics: Medicine
    Signatur Availability
    BibTip Others were also interested in ...
  • 45
    facet.materialart.
    facet.materialart.
    Wiley-Blackwell
    Publication Date: 2018-01-07
    Print ISSN: 0899-1987
    Electronic ISSN: 1098-2744
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 46
    Publication Date: 2018-01-08
    Description: Genotyping of classical major histocompatibility complex (MHC) genes is challenging when they are hypervariable and occur in multiple copies. In this study, we used several different approaches to genotype the moderately variable MHC class I exon 3 (MHCIe3) and the highly polymorphic MHC class II exon 2 (MHCIIβe2) in the bluethroat ( Luscinia svecica ). Two family groups (eight individuals) were sequenced in replicates at both markers using Ion Torrent technology with both a single- and a dual-indexed primer structure. Additionally, MHCIIβe2 was sequenced on Illumina MiSeq. Allele calling was conducted by modifications of the pipeline developed by Sommer et al. (BMC Genomics, 14, 2013, 542) and the software AmpliSAS. While the different genotyping strategies gave largely consistent results for MHCIe3, with a maximum of eight alleles per individual, MHCIIβe2 was remarkably complex with a maximum of 56 MHCIIβe2 alleles called for one individual. Each genotyping strategy detected on average 50%–82% of all MHCIIβe2 alleles per individual, but dropouts were largely allele-specific and consistent within families for each strategy. The discrepancies among approaches indicate PCR biases caused by the platform-specific primer tails. Further, AmpliSAS called fewer alleles than the modified Sommer pipeline. Our results demonstrate that allelic dropout is a significant problem when genotyping the hypervariable MHCIIβe2. As these genotyping errors are largely nonrandom and method-specific, we caution against comparing genotypes across different genotyping strategies. Nevertheless, we conclude that high-throughput approaches provide a major advance in the challenging task of genotyping hypervariable MHC loci, even though they may not reveal the complete allelic repertoire. Several different approaches were used to genotype the moderately variable MHC class I exon 3 (MHCIe3) and the highly polymorphic MHC class II exon 2 (MHCIIβe2) in the bluethroat, using replicates and family data. While the results were largely consistent for MHCIe3 among strategies, the different strategies rendered different results for MHCIIβe2.
    Electronic ISSN: 2045-7758
    Topics: Biology
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 47
    Publication Date: 2018-01-09
    Description: Solar urticaria (SU) is a rare photodermatosis occurring in response to exposure to ultraviolet–A (UVA), ultraviolet-B (UVB), visible and rarely infrared light. The condition typically affects adults (median age of onset 35 years), 1 with only one report of SU occurring in a 2-year-old. 2 Here we present five cases of SU occurring in childhood. This article is protected by copyright. All rights reserved.
    Print ISSN: 0007-0963
    Electronic ISSN: 1365-2133
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 48
    Publication Date: 2018-01-09
    Print ISSN: 0007-1048
    Electronic ISSN: 1365-2141
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 49
    Publication Date: 2018-01-09
    Description: In a previous study, we found that DNAJB8, a heat shock protein (HSP) 40 family member is expressed in kidney cancer stem-like cells (CSCs)/cancer-initiating cells (CICs) and that it has a role in the maintenance of kidney CSCs/CICs. Heat shock factor (HSF) 1 is a key transcription factor for responses to stress including heat shock, and it induces HSP family expression through activation by phosphorylation. In this study, we therefore examined whether heat shock (HS) induces CSCs/CICs. We treated the human kidney cancer cell line ACHN with HS, and found that HS increased side population (SP) cells. Western blot analysis and qRT-PCR showed that HS increased the expression of DNAJB8 and SOX2. Gene knockdown experiments using siRNAs showed that the increase in SOX2 expression and SP cell ratio depends on DNAJB8 and that the increase in DNAJB8 and SOX2 depend on HSF1. Furthermore, treatment with an mTOR inhibitor, temsirolimus, decreased the expression of DNAJB8 and SOX2 and the ratio of SP cells. Taken together, the results indicate that heat shock induces DNAJB8 by activation of HSF1 and induces cancer stem-like cells. This article is protected by copyright. All rights reserved.
    Topics: Medicine
    Signatur Availability
    BibTip Others were also interested in ...
  • 50
    Publication Date: 2018-01-09
    Description: Polychlorinated biphenyls (PCBs) are harmful and persistent organic pollutants that have long been used in industrial manufacturing. Their persistence leads to accumulation in the food chain causing potential toxic effects. As 19 out of 78 of the chiral congeners have stable atropisomers at ambient temperature, we studied some typical enantiomers: PCB45, PCB95, PCB136, and PCB149. The chiral stationary phases OD-H and OJ-H were used for separation in analytic high-performance liquid chromatography (HPLC), as well as for collection in semi-preparative HPLC. The resolution was optimized with respect to n -hexane–based mobile phases, temperature, and flow rate. All pure enantiomers were recovered from semi-preparative HPLC within 15 minutes for practical purpose. Characterization of the absolute configurations were conducted with a combination of theoretical and experimental electronic circular dichroism measurements. The enantiomers of PCB45, PCB95, PCB136, and PCB149 proved to be eluted as R  〉  S , S  〉  R , R  〉  S , and S  〉  R , respectively. Molecular structures (eg, substituent groups) and properties (eg, bond lengths, bond angles, and dipole moments) were quantitatively analyzed to understand the toxicity effect of PCBs. In summary, we have developed a well-established methodology of collection and configuration identification for analogous PCB derivatives.
    Print ISSN: 0899-0042
    Electronic ISSN: 1520-636X
    Topics: Chemistry and Pharmacology
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 51
    Publication Date: 2018-01-09
    Description: The enantiomeric resolution of DL-alanine-DL-tryptophan dipeptide is described on amylose stationary phase. The eluent used was CH 3 OH─CH 3 COONH 4 (10mM)─CH 3 CN (50: 40, 10) at 0.8-mL/min flow, 230-nm detection, 25-minute run time, and 25°C ± 1°C temperature. The chiral phase was amylose [AmyCoat RP (15 cm × 0.46 cm × 5 micron)]. The magnitudes of the retention factors (k) were 2.71, 3.52, 5.11, and 7.75. The magnitudes of separation factor (α) were 1.19, 1.57, and 1.51 while the resolution factors (Rs) were 3.25, 14.84, and 15.76. The limits of detection and quantitation were of 2.5 to 5.4 and 12.8 to 27.5 μg/mL. The enantiomeric resolution is controlled by hydrogen, hydrophobic, π-π, steric, etc interactions. The elution order of the enantiomer was supported by the modeling data. The described method is fast, reproducible, precise, and selective, which can be used successfully for evaluating the enantiomers of the reported dipeptide.
    Print ISSN: 0899-0042
    Electronic ISSN: 1520-636X
    Topics: Chemistry and Pharmacology
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 52
    Publication Date: 2018-01-07
    Description: Aim Blauvelt et al. (The Lancet 2017; 389: 2287-303) aimed to compare the long-term efficacy and safety of dupilumab with medium-potency topical corticosteroids (TCS) versus placebo with TCS in adults with moderate-to-severe atopic dermatitis (AD). Setting and design This multicentre randomised, double-blinded, placebo-controlled trial was conducted in hospitals, clinics and academic institutions across 161 sites in 14 countries. Study exposure Adults with moderate-to-severe AD were randomly assigned (3:1:3) to receive subcutaneous dupilumab 300mg once weekly (qw) plus TCS, dupilumab 300mg every 2 weeks (q2w) plus TCS, or placebo plus TCS until week-52. Primary outcome measures Co-primary efficacy endpoints were patients (%) achieving Investigator's Global Assessment (IGA) 0/1 and 2-points or higher improvement from baseline, and Eczema Area and Severity Index 75% improvement from baseline (EASI-75) at week-16. Results 740 patients were included in the trial: 319 were randomly assigned to dupilumab qw, 106 to dupilumab q2w and 315 to the placebo arm. At week-16, more patients in the dupilumab groups achieved the co-primary endpoints: IGA 0/1 (39% [125 patients] qw dosing, 39% [41 patients] q2w dosing vs 12% [39 patients] receiving placebo; p〈0.0001) and EASI-75 (64% [204] and 69% [73] vs 23% [73]; p〈0.0001). Whilst no new safety signals were identified, adverse effects (AEs) were noted in 261 (83%) in those receiving dupilumab qw plus TCS, 97 (88%) dupilumab q2w plus TCS and 266 (84%) for placebo plus TCS. Rates of conjunctivitis, injection site reactions and local herpes simplex infections were higher in the dupilumab groups compared with placebo. Conclusions Blauvelt et al . concluded that dupilumab treatment added to TCS improved AD up to week-52 compared with TCS alone, and also demonstrated acceptable safety. This article is protected by copyright. All rights reserved.
    Print ISSN: 0007-0963
    Electronic ISSN: 1365-2133
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 53
    facet.materialart.
    facet.materialart.
    Wiley-Blackwell
    Publication Date: 2018-01-09
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Signatur Availability
    BibTip Others were also interested in ...
  • 54
    Publication Date: 2018-01-09
    Description: Self-assembly of natural building blocks into complex 3D macromolecular structures plays a key role in living cells and other natural systems. Mimicking such self-assembly by synthetic (macro)molecules open new routes for the rational design of artificial smart materials. [1, 2] Particularly, block copolymers have received considerable attention due to their ability to self-assemble in bulk and solution into materials with applications ranging from technology to medicine. [3, 4 This article is protected by copyright. All rights reserved.
    Print ISSN: 0018-019X
    Electronic ISSN: 1522-2675
    Topics: Chemistry and Pharmacology
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 55
    Publication Date: 2018-01-09
    Description: ABSTRACT Current approaches to determine the cause of acute kidney injury (AKI) in patients with cirrhosis are suboptimal. The aim of this study was to determine the utility of fractional excretion of urea (FEUrea) for the differential diagnosis of AKI in cirrhotic patients. A retrospective analysis was performed in patients (n=50) with cirrhosis and ascites admitted with AKI. Using adjudicated etiology assessment as the reference standard, receiver operating curves (ROC) and optimal cutoff, sensitivity (Sn) and specificity (Sp) for the diagnosis of prerenal azotemia (PRA), type 1 hepatorenal syndrome (HRS) and acute tubular necrosis (ATN) was derived. Validation was performed in an independent cohort (n=50) and by bootstrap analysis. The causes of AKI (derivation:validation cohorts) were: PRA 21:21, HRS 18:15, ATN: 11:14. Median FEUrea were statistically different across all etiologies of AKI in the derivation cohort (PRA 30.1 vs HRS 20.2 vs ATN 43.6, p=〈0.001) and validation cohort (PRA 23.1 vs HRS 13.3 vs ATN 44.7, p=〈0.001). The AUC (cutoff, Sn/Sp) for FEUrea was 0.96 (33.4, 85/100) for ATN vs non-ATN, 0.87 (28.7, 75/83) for HRS vs non-HRS, and 0.81 (21.6, 90/61) for PRA vs HRS. When applied to the validation cohort, the Sn/Sp were maintained for ATN vs non-ATN (93/97), HRS vs non-HRS (100/63), and for PRA vs HRS (67/80). After bootstrapping, the Sn/Sp for FEUrea in the ATN vs non-ATN, HRS vs non-HRS, and PRA vs HRS was 88/96, 63/97, and 55/87 respectively. Conclusions: FEUrea is a promising tool for the differential diagnosis of AKI in patients with cirrhosis. This article is protected by copyright. All rights reserved.
    Print ISSN: 0270-9139
    Electronic ISSN: 1527-3350
    Topics: Medicine
    Signatur Availability
    BibTip Others were also interested in ...
  • 56
    Publication Date: 2018-01-09
    Description: A strong positive association has been observed between circulating anti-Müllerian hormone (AMH), a biomarker of ovarian reserve, and breast cancer risk in three prospective studies. Confirming this association is important because of the paucity of biomarkers of breast cancer risk in premenopausal women. We conducted a consortium study including ten prospective cohorts that had collected blood from premenopausal women. A nested case-control design was implemented within each cohort. A total of 2,835 invasive (80%) and in situ (20%) breast cancer cases were individually matched to controls (n = 3,122) on age at blood donation. AMH was measured using a high sensitivity enzyme-linked immunoabsorbent assay. Conditional logistic regression was applied to the aggregated dataset. There was a statistically significant trend of increasing breast cancer risk with increasing AMH concentration (p trend across quartiles 〈 0.0001) after adjusting for breast cancer risk factors. The odds ratio (OR) for breast cancer in the top versus bottom quartile of AMH was 1.60 (95% CI = 1.31-1.94). Though the test for interaction was not statistically significant (p interaction = 0.15), the trend was statistically significant only for tumors positive for both estrogen receptor (ER) and progesterone receptor (PR): ER+/PR+: OR Q4-Q1 = 1.96, 95% CI = 1.46-2.64, p trend 〈0.0001; ER+/PR-: OR Q4-Q1 = 0.82, 95% CI = 0.40-1.68, p trend = 0.51; ER-/PR+: OR Q4-Q1 = 3.23, 95% CI =0.48-21.9, p trend = 0.26; ER-/PR-: OR Q4-Q1 = 1.15, 95% CI = 0.63-2.09, p trend = 0.60. The association was observed for both pre- (OR Q4-Q1 = 1.35, 95% CI= 1.05-1.73) and post-menopausal (OR Q4-Q1 =1.61, 95% CI = 1.03 - 2.53) breast cancer (p interaction = 0.34). In this large consortium study, we confirmed that AMH is associated with breast cancer risk, with a 60% increase in risk for women in the top vs. bottom quartile of AMH. This article is protected by copyright. All rights reserved.
    Print ISSN: 0020-7136
    Electronic ISSN: 1097-0215
    Topics: Biology , Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 57
    Publication Date: 2018-01-09
    Print ISSN: 0007-1048
    Electronic ISSN: 1365-2141
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 58
    Publication Date: 2018-01-09
    Description: We report a multicentre retrospective study that analysed clinical characteristics and outcomes in 117 patients with primary plasma cell leukaemia (pPCL) treated at the participating institutions between January 2006 and December 2016. The median age at the time of pPCL diagnosis was 61 years. Ninety-eight patients were treated with novel agents, with an overall response rate of 78%. Fifty-five patients (64%) patients underwent upfront autologous stem cell transplantation (ASCT). The median follow-up time was 50 months (95% confidence interval [CI] 33; 76), with a median overall survival (OS) for the entire group of 23 months (95% CI 15; 34). The median OS time in patients who underwent upfront ASCT was 35 months (95% CI 24·3; 46) as compared to 13 months (95% CI 6·3; 35·8) in patients who did not receive ASCT ( P  =   0·001). Multivariate analyses identified age ≥60 years, platelet count ≤100 × 10 9 /l and peripheral blood plasma cell count ≥20 × 10 9 /l as independent predictors of worse survival. The median OS in patients with 0, 1 or 2–3 of these risk factors was 46, 27 and 12 months, respectively ( P  〈   0·001). Our findings support the use of novel agents and ASCT as frontline treatment in patients with pPCL. The constructed prognostic score should be independently validated.
    Print ISSN: 0007-1048
    Electronic ISSN: 1365-2141
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 59
    Publication Date: 2018-01-09
    Description: To investigate the potential biomarkers associated with Chronic Myeloid Leukemia (CML), reveal the metabolite changes related to the continuous phases of tyrosine kinase inhibitors (TKI) and find the potential biomarkers associated with treatment effects. 52 patients with CML and matched 26 healthy people were enrolled as discovery set. Another 194 randomly selected CML patients treated with TKI were chosen as external validation set. Plasma samples from the patients and controls were profiled by using gas chromatography-mass spectrometry (GC-MS) based metabonomic approach. Multivariate and univariate statistical analysis were combined to select the differential metabolic features. GC-MS-based metabolomics showed a clear clustering and separation of metabolic patterns from healthy control, pre- and post-TKI treatment CML patients in the discovery set. We identified nine metabolites that differentiated CML patients from healthy controls, including lactic acid, isoleucine, glycerol, glycine, myristic acid, D-sorbitol, D-galactose, D-glucose and myo-inositol. Among the 9 markers, glycerol and myristic acid had the most significant association with TKI treatment effects in both discovery and external validation set. In the ROC analysis, combination of glycerol and myristic acid showed a better discrimination performance compared to a single biomarker. The results indicated that metabolic profile has the potential for diagnosis of CML and the panel of biomarkers including myristic acid and glycerol may be useful in monitoring TKI therapeutic responses. This article is protected by copyright. All rights reserved.
    Topics: Medicine
    Signatur Availability
    BibTip Others were also interested in ...
  • 60
    Publication Date: 2018-01-09
    Description: Oesophageal cancer (OC) is one of the most fatal malignancies in the world, and chemoresistance restricts the therapeutic outcome of OC. Long noncoding RNA (lncRNA) was reported to play roles in multiple cancer types. Yet, the function of lncRNA in chemoresistance of OC has not been reported. A lncRNA gene, PCAT-1, showed higher expression in OC tissues, especially higher in secondary OC compared with normal mucosa tissues. Overexpression of PCAT-1 increased the proliferation rate and growth of OC cells. Inhibition of PCAT-1 decreased proliferation and growth of OC cells, and increased cisplatin chemosensitivity. In a mouse OC xenograft model, PCAT-1 inhibition repressed OC growth in vivo. Therefore, PCAT-1 may potentially serve as a therapeutic target for treating OC. PCAT-1 promotes development of OC and represses the chemoresistance of OC to cisplatin, and silencing of PCAT-1 may be a therapeutic strategy for treating OC.
    Print ISSN: 0263-6484
    Electronic ISSN: 1099-0844
    Topics: Biology , Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 61
    Publication Date: 2018-01-09
    Description: Underground community assemblies have not been studied well compared with aboveground communities, despite their importance for our understanding of whole ecosystems. To investigate underground community assembly over evolutionary timescales, we examined terrestrial earthworm communities (Oligochaeta: Haplotaxida) in conserved mountainous primary forests in Japan as a model system. We collected 553 earthworms mostly from two dominant families, the Megascolecidae and the Lumbricidae, from 12 sites. We constructed a molecular taxonomic unit tree based on the analysis of three genes to examine the effects of a biogeographic factor (dispersal ability) and an evolutionary factor (habitat adaptation) on the earthworm community assembly process. The phylogenetic distance of the earthworm communities among sites was positively correlated with geographic distance when intraspecific variation was included, indicating that the divergence within species was affected by biogeographic factors. The community assembly process in the Megascolecidae has also been affected by environmental conditions in relation to an evolutionary relationship between habitat environment and intestinal cecum type, a trait closely related to habitat depth and diet, whereas that in the Lumbricidae has not been affected as such. Intestinal cecum type showed a pattern of niche conservatism in the Megascolecidae lineage. Our results suggest that investigating the evolution of a key trait related to life history can lead to the clear description of community assembly process over a long timescale and that the community assembly process can differ greatly among related lineages even though they live sympatrically. To investigate underground community assembly over evolutionary time scales, we examined terrestrial earthworm communities (Oligochaeta: Haplotaxida) in conserved mountainous primary forests in Japan. Our study shows that the community assembly process in the Megascolecidae, which is one of the two dominant families in Japan, has been affected by environmental factors in relation to an evolutionary relationship between habitat environment and intestinal cecum type, a trait closely related to habitat depth and diet, whereas that in the Lumbricidae has not been affected as such. Our results suggest that investigating the evolution of a key trait related to life history can lead to the clear description of community assembly process and that the community assembly process can differ greatly among related lineages even though they live sympatrically.
    Electronic ISSN: 2045-7758
    Topics: Biology
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 62
    Publication Date: 2018-01-09
    Description: Food resources are often not sufficient to satisfy the nutritional and energetic requirements during winter conditions at high latitudes. Dietary analysis is a prerequisite to fully understanding the feeding ecology of a species and the nature of trophic interactions. Previous dietary studies of Asian Great Bustard ( Otis tarda dybowskii ) relied on behavioral observations, resulting in categorization of diet limited to broad taxonomic groupings. Here, we applied a high-throughput sequencing meta-barcoding approach to quantify the diet of resident and migratory Asian Great Bustard in three wintering sites during early winter and late winter. We detected 57 unique plant taxa in the bustard diet, among which 15 species were confirmed by a local plant database we generated. Both agricultural and natural foods were detected, indicating a relatively broad dietary niche. Spatiotemporal dietary changes were discovered, revealing diet differences among wintering sites and a general shift toward lower plant diversity later in winter. For the nonmigratory population, we detected a significantly more diverse array of plant species in their diet. We hypothesize that dietary variation between resident and migratory populations could be involved in the recent transition to partial migration in this species, although climate change can not be excluded. Collectively, these results support protecting unharvested grain fields and naturally unplowed lands to help conserve and promote population growth of Asian Great Bustard. Previous studies on the diet of Asian Great Bustard ( Otis tarda dybowskii ) relied only on behavioral observation, resulting in superficial knowledge of diet limited to broad taxonomic. We applied the high-throughput sequencing (HTS) approach to the analysis of the plant component of resident and migratory Asian Great Bustard diet in three wintering sites during early winter and late winter. Spatiotemporal dietary changes were discovered, revealing an interactive effect of wintering site and wintering time on diets of Asian Great Bustards.
    Electronic ISSN: 2045-7758
    Topics: Biology
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 63
    Publication Date: 2018-01-09
    Description: Proteostasis imbalance is emerging as a major hallmark of cancer, driving tumor aggressiveness. Evidence suggests that the endoplasmic reticulum (ER), a major site for protein folding and quality control, plays a critical role in cancer development. This concept is valid in glioblastoma multiform (GBM), the most lethal primary brain cancer with no effective treatment. We previously demonstrated that the ER stress sensor IRE1α (referred to as IRE1) contributes to GBM progression, through XBP1 mRNA splicing and regulated IRE1-dependent decay (RIDD) of RNA. Here, we first demonstrated IRE1 signaling significance to human GBM and defined specific IRE1-dependent gene expression signatures that were confronted to human GBM transcriptomes. This approach allowed us to demonstrate the antagonistic roles of XBP1 mRNA splicing and RIDD on tumor outcomes, mainly through selective remodeling of the tumor stroma. This study provides the first demonstration of a dual role of IRE1 downstream signaling in cancer and opens a new therapeutic window to abrogate tumor progression. The IRE1 arm of the Unfolded Protein Response (UPR) plays a major role in cancer development. Dissecting IRE1 signals in human glioblastoma tumors, primary and established cell lines reveals the dual role of XBP1 mRNA splicing and RIDD in tumor aggressiveness.
    Print ISSN: 1757-4676
    Electronic ISSN: 1757-4684
    Topics: Medicine
    Signatur Availability
    BibTip Others were also interested in ...
  • 64
    facet.materialart.
    facet.materialart.
    Wiley-Blackwell
    Publication Date: 2018-01-09
    Description: Invadosomes in health and disease, by E. K. Paterson and S. A. Courtneidge (pp. 8 – 27).
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Signatur Availability
    BibTip Others were also interested in ...
  • 65
    Publication Date: 2018-01-09
    Description: Expansion and death of effector CD8 T cells are regulated to limit immunopathology and cells that escape contraction go on to generate immunological memory. CD44, a receptor for the extracellular matrix component hyaluronan, is a marker of activated and memory T cells. Here, we show with a murine model that the increase in CD44 expression and hyaluronan binding induced upon CD8 T cell activation was proportional to the strength of TCR engagement, thereby identifying the most strongly activated T cells. When CD44 −/− and CD44 +/+ OT-I CD8 T cells were adoptively transferred into mice challenged with Listeria -OVA, there was a slight increase in the percentage of CD44 +/+ cells at the effector site. However, CD44 +/+ cells were out-competed by CD44 −/− cells after the contraction phase in the lymphoid tissues, and the CD44 −/− cells preferentially formed more memory cells. The hyaluronan-binding CD44 +/+ CD8 effector T cells showed increased pAkt expression, higher glucose uptake, and were more susceptible to cell death during the contraction phase compared to non-binding CD44 +/+ and CD44 −/− OT-I CD8 T cells, suggesting that CD44 and its engagement with hyaluronan skews CD8 T cells towards a terminal effector differentiation state that reduces their ability to form memory cells. This article is protected by copyright. All rights reserved
    Print ISSN: 0014-2980
    Electronic ISSN: 1521-4141
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 66
    Publication Date: 2018-01-09
    Description: Background : Acute lung injury is a life-threatening inflammatory lung condition. Studies have explored the role of lncRNA H19 in several diseases, including cancers. In this study, We aimed to explore the role of H19 in lipopolysaccharide (LPS)-induced lung injury and to elucidate the underlying molecular mechanism. Methods : MRC-5 cells (lung fibroblast cells) were used in the experiment. Cell viability, proliferation, and apoptosis were measured by specific assays. qRT PCR and western blot estimated specific mRNAs and proteins, respectively. Short-hairpin RNA directed against human lncRNA H19 was ligated into plasmid and referred to as (sh-H19). Aagin, full-length Runx2 sequences and short-hairpin RNA directed against Runx2 were constructed in pEX-2 and plasmids respectively, and were referred as to pEX-Runx2 and sh-Runx2 Results : LPS significantly suppressed cell viability (P 〈 0.05) and migration (P 〈 0.01), and increased apoptosis (P 〈 0.001). LPS also significantly increased (p 〈 0.01) expression of H19. Suppression of H19 expression led to significant decrease in cell viability, migration and significant increase in apoptosis (P 〈 0.05). Although suppression of H19 was deleterious to cells, suppression of both miR181a and H19 led to opposite changes. Knockdown of miR-181a led to upregulation of Runx2 expression, which significantly improved (P 〈 0.05) cell viability, migration, and suppressed (P 〈 0.05) apoptosis. Overexpression of Runx2 also activated Notch and JNK pathways. Conclusion : H19 protected MRC-5 cells against LPS mediated cell injury by suppressing miR181 expression which in turn acts via promotion of Runx2 expression. Again, overexpression of Runx2 led to activation of Notch and JNK pathways. This article is protected by copyright. All rights reserved
    Electronic ISSN: 0091-7419
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 67
    Publication Date: 2018-01-09
    Description: Peripheral myelin protein 22 (PMP22) is a component of compact myelin in the peripheral nervous system. The amount of PMP22 in myelin is tightly regulated, and PMP22 over or under-expression cause Charcot-Marie-Tooth 1A (CMT1A) and Hereditary Neuropathy with Pressure Palsies (HNPP). Despite the importance of PMP22 , its function remains largely unknown. It was reported that PMP22 interacts with the β4 subunit of the laminin receptor α6β4 integrin, suggesting that α6β4 integrin and laminins may contribute to the pathogenesis of CMT1A or HNPP. Here we asked if the lack of α6β4 integrin in Schwann cells influences myelin stability in the HNPP mouse model. Our data indicate that PMP22 and β4 integrin may not interact directly in myelinating Schwann cells, however, ablating β4 integrin delays the formation of tomacula, a characteristic feature of HNPP. In contrast, ablation of integrin β4 worsens nerve conduction velocities and non-compact myelin organization in HNPP animals. This study demonstrates that indirect interactions between an extracellular matrix receptor and a myelin protein influence the stability and function of myelinated fibers. This article is protected by copyright. All rights reserved.
    Print ISSN: 0022-3042
    Electronic ISSN: 1471-4159
    Topics: Medicine
    Signatur Availability
    BibTip Others were also interested in ...
  • 68
    Publication Date: 2018-01-09
    Description: Parkinson's disease (PD) is marked clinically by motor dysfunction and pathologically by dopaminergic cell loss in the substantia nigra (SN) and iron accumulation in the substantia nigra. The driver underlying iron accumulation is unknown and could be genetic or environmental. The HFE protein is critical for the regulation of cellular iron uptake. Mutations within this protein are associated with increased iron accumulation including in the brain. We have focused on the commonly occurring H63D variant of the HFE gene as a disease modifier in a number of neurodegenerative diseases. To investigate the role of H63D HFE genotype, we generated a mouse model in which the wild-type (WT) HFE gene is replaced by the H67D gene variant (mouse homolog of the human H63D gene variant). Using paraquat toxicity as the model for Parkinson's disease, we found that WT mice responded as expected with significantly greater motor function, loss of tyrosine hydroxylase staining and increase microglial staining in the substantia nigra, and an increase in R 2 relaxation rate within the substantia nigra of the paraquat-treated mice compared to their saline-treated counterparts. In contrast, the H67D mice showed a remarkable resistance to paraquat treatment; specifically differing from the WT mice with no changes in motor function or changes in R 2 relaxation rates following paraquat exposure. At baseline, there were differences between the H67D HFE mice and WT mice in gut microbiome profile and increased L-ferritin staining in the substantia nigra that could account for the resistance to paraquat. Of particular note, the H67D HFE mice regardless of whether or not they were treated with paraquat had significantly less tyrosine hydroxylase immunostaining than WT. Our results clearly demonstrate that the HFE genotype impacts the expression of tyrosine hydroxylase in the substantia nigra, the gut microbiome and the response to paraquat providing additional support that the HFE genotype is a disease modifier for PD. Moreover, the finding that the HFE mutant mice are resistant to paraquat may provide a model in which to study resistant mechanisms to neurotoxicants. This article is protected by copyright. All rights reserved.
    Print ISSN: 0022-3042
    Electronic ISSN: 1471-4159
    Topics: Medicine
    Signatur Availability
    BibTip Others were also interested in ...
  • 69
    Publication Date: 2018-01-09
    Description: Loss of function mutations of DJ-1 ( PARK7 ) have been linked to the pathogenesis of Parkinson disease (PD). Antioxidative stress is one of the multi-protective functions of DJ-1, and oxidation of cysteine 106 (Cys106) has been proposed to regulate the protective activity of DJ-1. Uncoupling protein 4 (UCP4) is located in the inner membrane of mitochondria and functions to protect against oxidative stress. In this study, we used neuronal (SH-SY5Y) cells and DJ-1 knockout (KO) mice to elucidate whether DJ-1 regulated oxidative stress via modulating the expression of UCP4, and the underlying mechanism. The downstream products of oxidative stress, mitochondrial membrane potential (ΔΨm) and cell viability were also investigated. We found that UCP4 was up regulated upon 1-methyl-4-phenylpyridinium (MPP + ) stimulation in SH-SY5Y cells, which was enhanced by wild type DJ-1 and alleviated by DJ-1 knockdown. Expression of UCP4 in DJ-1 KO mice was lower compared with wild type mice. In addition, up-regulation of UCP4 was alleviated by inhibition of oxidized DJ-1, and enhanced by increase of oxidized DJ-1 under conditions of oxidative stress using western blot analysis. Moreover, overexpression of UCP4 in DJ-1 knockdown cells partially reversed the decrease of cell viability, ΔΨm, as well as the increase of products of oxidative stress upon MPP + stimulation. Further analysis showed that DJ-1 regulated transcriptional activity of UCP4 partially via Nuclear factor-kappa B (NF-κB) pathway in the presence of MPP + . Together, our results suggested DJ-1 might regulate the expression of UCP4 by oxidation of DJ-1 and partially via NF-κB pathway in its protective response to oxidative stress. This article is protected by copyright. All rights reserved.
    Print ISSN: 0022-3042
    Electronic ISSN: 1471-4159
    Topics: Medicine
    Signatur Availability
    BibTip Others were also interested in ...
  • 70
    Publication Date: 2018-01-09
    Description: Purpose To evaluate the role of true diffusion and flow-related pseudodiffusion in cerebral blood flow (CBF) quantification using arterial spin labeling (ASL) with single-shot or segmented 3D gradient and spin echo (GRASE) readouts. Theory The extended phase graph (EPG) algorithm, originally designed to model the effects of T 1 /T 2 relaxation and true diffusion in MRI acquisitions utilizing multiple refocusing RF pulses, was augmented (aEPG). This augmentation accounted for flow-related pseudodiffusion attenuation of intravascular MRI signal in the k-space domain during 3D-GRASE acquisition, which leads to blur along the partition direction in the image domain. Blurring of ASL signal into neighboring voxels can lead to underestimation of CBF in small, high-flow structures such as cortical gray matter (GM). Methods The diffusion sensitivity of 3D-GRASE was evaluated through aEPG simulations and in vivo experiments in 13 healthy subjects. The CBF estimation bias for different postlabeling delays, crusher gradient strengths, and segmentation factors along the partition (PAR) and phase-encoding (PE) directions was numerically assessed by simulations and experimentally validated. Results In vivo experiments demonstrated systematic underestimation of mean GM CBF measured with segmented 3D-GRASE. The GM CBF underestimation depended on ASL preparation and imaging parameters; it reached up to 25% at low-segmentation schemes (1 PAR  × 2 PE ) but was considerably lower at high-segmentation schemes (4 PAR  × 2 PE or 8 PAR  × 2 PE ). Theoretical predictions showed that conventional T 1 /T 2 relaxation and true diffusion may account for at most ∼25% of GM CBF estimation bias, whereas the pseudodiffusion effect constituted the major fraction in a typical ASL experiment. Conclusion The pseudodiffusion effect leads to considerable estimation bias in ASL-based CBF quantification using 3D-GRASE readouts. This bias can be substantially reduced by increasing the segmentation factors. Magn Reson Med, 2018. Published 2018. This article is a U.S. Government work and is in the public domain in the USA.
    Print ISSN: 0740-3194
    Electronic ISSN: 1522-2594
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 71
    Publication Date: 2018-01-09
    Description: Fumarate is an important probe of metabolism in hyperpolarized magnetic resonance imaging and spectroscopy. It is used to detect the release of fumarase in cancer tissues, which is associated with necrosis and drug treatment. Nevertheless, there are limited reports describing the detailed kinetic studies of this enzyme in various cells and tissues. Thus, we aimed to evaluate the sub-minute kinetics of human red blood cell fumarase using nuclear magnetic resonance (NMR) spectroscopy, and to provide a quantitative description of the enzyme that is relevant to the use of fumarate as a probe of cell rupture. The fumarase reaction was studied using time courses of 1 H spin-echo and 13 C-NMR spectra. 1 H-NMR experiments showed that the fumarase reaction in hemolysates is sufficiently rapid to make its kinetics amenable to study in a period of approximately 3 min, a timescale characteristic of hyperpolarized 13 C-NMR spectroscopy. The rapid-dissolution dynamic nuclear polarization (RD-DNP) technique was used to hyperpolarize [1,4- 13 C]fumarate, which was injected into concentrated hemolysates. The kinetic data were analyzed using recently developed FmR α analysis and modeling of the enzymatic reaction using Michaelis–Menten equations. In RD-DNP experiments, the decline in the 13 C-NMR signal from fumarate, and the concurrent rise and fall of that from malate, were captured with high spectral resolution and signal-to-noise ratio, which allowed the robust quantification of fumarase kinetics. The kinetic parameters obtained indicate the potential contribution of hemolysis to the overall rate of the fumarase reaction when 13 C-NMR RD-DNP is used to detect necrosis in animal models of implanted tumors. The analytical procedures developed will be applicable to studies of other rapid enzymatic reactions using conventional and hyperpolarized substrate NMR spectroscopy. The sub-minute kinetics of human red blood cell fumarase was evaluated using 1 H spin-echo and 13 C-nuclear magnetic resonance (NMR) spectroscopy. The kinetic parameters obtained indicate the potential contribution of hemolyzed blood to the overall rate of the fumarase reaction when hyperpolarized 13 C-NMR spectroscopy is used to detect necrosis in animal models of implanted tumors. The developed analytical procedures will be applicable to studies of other rapid enzymatic reactions using conventional and hyperpolarized NMR spectroscopy.
    Print ISSN: 0952-3480
    Electronic ISSN: 1099-1492
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 72
    Publication Date: 2018-01-09
    Description: Background Distinguishing between low- and high-grade prostate cancers (PCa) is important, but biopsy may underestimate the actual grade of cancer. We have previously shown that urine/plasma-based prostate-specific biomarkers can predict high grade PCa. Our objective was to determine the accuracy of a test using cell-free RNA levels of biomarkers in predicting prostatectomy results. Methods This multicenter community-based prospective study was conducted using urine/blood samples collected from 306 patients. All recruited patients were treatment-naïve, without metastases, and had been biopsied, designated a Gleason Score (GS) based on biopsy, and assigned to prostatectomy prior to participation in the study. The primary outcome measure was the urine/plasma test accuracy in predicting high grade PCa on prostatectomy compared with biopsy findings. Sensitivity and specificity were calculated using standard formulas, while comparisons between groups were performed using the Wilcoxon Rank Sum, Kruskal-Wallis, Chi-Square, and Fisher's exact test. Results GS as assigned by standard 10-12 core biopsies was 3 + 3 in 90 (29.4%), 3 + 4 in 122 (39.8%), 4 + 3 in 50 (16.3%), and 〉 4 + 3 in 44 (14.4%) patients. The urine/plasma assay confirmed a previous validation and was highly accurate in predicting the presence of high-grade PCa (Gleason ≥3 + 4) with sensitivity between 88% and 95% as verified by prostatectomy findings. GS was upgraded after prostatectomy in 27% of patients and downgraded in 12% of patients. Conclusions This plasma/urine biomarker test accurately predicts high grade cancer as determined by prostatectomy with a sensitivity at 92-97%, while the sensitivity of core biopsies was 78%.
    Print ISSN: 0270-4137
    Electronic ISSN: 1097-0045
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 73
    Publication Date: 2018-01-10
    Description: Background Incontinence-associated dermatitis (IAD) is a specific type of irritant contact dermatitis with different levels of severity. An internationally accepted instrument to assess the severity of IAD in adults with established diagnostic accuracy, agreement, and reliability is needed to support clinical practice and research. Objectives To design and psychometrically evaluate the Ghent Global IAD Categorisation Tool (GLOBIAD). Methods The design was based on expert consultation using a three-round Delphi procedure with 34 experts from 13 countries. The instrument was tested using IAD photographs reflecting different severity levels in a sample of 823 health professionals in 30 countries. Measures for diagnostic accuracy (sensitivity and specificity), agreement, inter-rater reliability (multi-rater Fleiss kappa), and intra-rater reliability (Cohen's Kappa) were assessed. Results The GLOBIAD consists of two categories according to the presence of persistent redness (Cat.1) and skin loss (Cat.2), both subdivided based on the presence of clinical signs of infection. The agreement for differentiating between Cat.1 and Cat.2 was 0.86 [95% confidence interval (CI) 0.86-0.87], with a sensitivity of 90% and a specificity of 84%. The overall agreement was 0.55 (95%CI 0.55-0.56). The Fleiss Kappa for differentiating between Cat.1 and Cat.2 was 0.65 (95%CI 0.65-0.65). The overall Fleiss Kappa was 0.41 (95%CI 0.41-0.41). The Cohen's Kappa for differentiating between Cat.1 and Cat.2 was 0.76 (95%CI 0.75-0.77). The overall Cohen's Kappa was 0.61 (95%CI 0.59-0.62). Conclusions The development of the GLOBIAD is a major step forward towards a better systematic assessment of IAD in clinical practice and research worldwide. Further validation is however needed. This article is protected by copyright. All rights reserved.
    Print ISSN: 0007-0963
    Electronic ISSN: 1365-2133
    Topics: Medicine
    Published by Wiley-Blackwell
    Signatur Availability
    BibTip Others were also interested in ...
  • 74
    Publication Date: 2018-01-10
    Description: BACKGROUND Time to treatment initiation (TTI) is increasing and is associated with worsening survival. In the current study, the authors sought to identify a mechanism for this relationship by assessing the effect of TTI on clinical-to-pathologic upstaging in patients with head and neck squamous cell carcinoma (HNSCC). METHODS Using the National Cancer Data Base, the authors analyzed patients receiving definitive surgery for SCC of the oral cavity, oropharynx, larynx, and hypopharynx from 2005 through 2014. The primary outcome was T, N, or stage group upstaging, defined as higher pathologic stage than clinical stage. TTI was defined as the time between diagnosis and surgery. Multivariable logistic and Cox proportional hazards regression modeled upstaging and survival, respectively. RESULTS Cohorts of 60,194 patients, 51,380 patients, and 52,980 patients, respectively, with complete T, N, and stage group data were included. N upstaging was most common (18.6%), followed by stage group (17.4%) and T (12.1%) upstaging; all types were predicted by TTI. Compared with a TTI of 1 to 6 days, TTIs as short as 7 to 13 days (odds ratio, 1.20; P  = .038) or ≥ 70 days (odds ratio, 2.04; P  〈 .001) were found to predict T upstaging, a finding that is consistent for N and stage group upstaging. Using restricted cubic splines, relative odds of T and stage group upstaging escalated to 2.25 and 1.93, respectively, at a TTI of 365 days. In survival analyses, T (hazard ratio [HR], 1.53), N (HR, 1.88), and stage group (HR, 1.69) upstaging all predicted mortality ( P  〈 .001), whereas TTI only predicted mortality after 70 days (HR, 1.11; P  = .023). CONCLUSIONS Tumor progression, measured by clinical-to-pathologic upstaging, increases mortality for patients with HNSCC experiencing treatment delays. Cancer 2018 . © 2018 American Cancer Society .
    Print ISSN: 0008-543X
    Electronic ISSN: 1097-0142
    Topics: Biology , Medicine
    Published by Wiley-Blackwell on behalf of The American Cancer Society.
    Signatur