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  • Wiley-Blackwell  (95,087)
  • 2015-2019  (2,471)
  • 1990-1994  (66,069)
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  • 1
    Publication Date: 2018-02-17
    Description: Suboptimal environmental conditions are ubiquitous in nature and commonly drive the outcome of biological interactions in community processes. Despite the importance of biological interactions for community processes, knowledge on how species interactions are affected by a limiting resource, for example, low food availability, remains limited. Here, we tested whether variation in food supply causes nonadditive consumption patterns, using the macroinvertebrate community of intertidal sandy beaches as a model system. We quantified isotopically labeled diatom consumption by three macroinvertebrate species ( Bathyporeia pilosa , Haustorius arenarius, and Scolelepis squamata ) kept in mesocosms in either monoculture or a three-species community at a range of diatom densities. Our results show that B. pilosa was the most successful competitor in terms of consumption at both high and low diatom density, while H. arenarius and especially S. squamata consumed less in a community than in their respective monocultures. Nonadditive effects on consumption in this macroinvertebrate community were present and larger than mere additive effects, and similar across diatom densities. The underlying species interactions, however, did change with diatom density. Complementarity effects related to niche-partitioning were the main driver of the net diversity effect on consumption, with a slightly increasing contribution of selection effects related to competition with decreasing diatom density. For the first time, we showed that nonadditive effects of consumption are independent of food availability in a macroinvertebrate community. This suggests that, in communities with functionally different, and thus complementary, species, nonadditive effects can arise even when food availability is low. Hence, at a range of environmental conditions, species interactions hold important potential to alter ecosystem functioning. To test whether variation in food supply causes nonadditive consumption patterns, we quantified isotopically labeled diatom consumption by three intertidal macroinvertebrate species kept in mesocosms in either monoculture or a community at a range of diatom densities. Complementarity effects on consumption were the main driver of the net diversity effect, with a slightly increasing contribution of selection effects with decreasing diatom density. For the first time, we have shown that nonadditive effects of consumption are independent from food availability in a macroinvertebrate community.
    Electronic ISSN: 2045-7758
    Topics: Biology
    Published by Wiley-Blackwell
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  • 2
    Publication Date: 2018-02-27
    Description: The purpose of this study was to measure the sodium transverse relaxation time T 2 * in the healthy human brain. Five healthy subjects were scanned with 18 echo times (TEs) as short as 0.17 ms. T 2 * values were fitted on a voxel-by-voxel basis using a bi-exponential model. Data were also analysed using a continuous distribution fit with a region of interest-based inverse Laplace transform. Average T 2 * values were 3.4 ± 0.2 ms and 23.5 ± 1.8 ms in white matter (WM) for the short and long components, respectively, and 3.9 ± 0.5 ms and 26.3 ± 2.6 ms in grey matter (GM) for the short and long components, respectively, using the bi-exponential model. Continuous distribution fits yielded results of 3.1 ± 0.3 ms and 18.8 ± 3.2 ms in WM for the short and long components, respectively, and 2.9 ± 0.4 ms and 17.2 ± 2 ms in GM for the short and long components, respectively. 23 Na T 2 * values of the brain for the short and long components for various anatomical locations using ultra-short TEs are presented for the first time. Healthy subjects were scanned using 23 Na ultra-short echo time (UTE) magnetic resonance imaging (MRI) with 18 TEs between 0.17 and 67 ms. T 2 * values were fitted on a voxel-by-voxel basis using a bi-exponential model and using a continuous distribution fit with a region of interest-based inverse Laplace transform. Detailed 23 Na T 2 * values of the brain for the short and long components for various anatomical locations using UTEs are presented for the first time.
    Print ISSN: 0952-3480
    Electronic ISSN: 1099-1492
    Topics: Medicine
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  • 3
    Publication Date: 2018-02-28
    Description: A patient in whom organs or molecules are affected sequentially by an autoimmune response prompted us to propose a hypothesis that epitope spreading may account for the sequential involvement of different cells. A 27-year old male patient was diagnosed in January 2005 with idiopathic thrombocytopenic purpura (ITP), since all autoantibodies relevant to autoimmune diseases were negative. He was treated with immunosuppression and spenectomy. In 2014, the patient developed transient blurred vision, dizziness and walking instability and autoimmune chylomicronemia was diagnosed, based on the presence of autoantibodies to lipoprotein lipase (LPL) (1). This article is protected by copyright. All rights reserved.
    Print ISSN: 0300-9475
    Electronic ISSN: 1365-3083
    Topics: Medicine
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  • 4
    Publication Date: 2018-02-28
    Description: Sepsis is a condition caused by infection followed by unregulated inflammatory response which may lead to the organ dysfunction. During such condition, over-production of oxidants is one of the factors which contribute cellular toxicity and ultimately organ failure and mortality. Antioxidants having free radicals scavenging activity exert protective role in various diseases. The present study has been designed to evaluate the levels of oxidative and anti-oxidative activity in sepsis patients and their correlation with the severity of the sepsis. A total of 100 sepsis patients and 50 healthy controls subjects were enrolled in this study from the period October 2016 to June 2017. The investigation included measurements of oxidative enzyme, myeloperoxidase (MPO), antioxidant enzymes including superoxide dismutase activity (SOD) and catalase activity (CAT) and cytokines (TNF-α, IL-8 and IFN-γ). Furthermore, the level of these activities was correlated with severity of sepsis. Augmented levels of oxidants were found in sepsis as demonstrated by DMPO nitrone adduct formation and plasma MPO level activity (1.37 ± 0.51 in sepsis vs 0.405 ± 0.16 in control subjects). Cytokines were also found to be increased in sepsis patients. However, plasma SOD and CAT activities were significantly attenuated (p〈0.001) in the sepsis patients compared with controls subjects. Moreover, inverse relation between antioxidant enzymes (SOD and CAT) and organ failure assessment (SOFA), physiological score (APACHE II), organ toxicity specific markers have been observed as demonstrated by Pearson's correlation coefficient. This study suggests that imbalance between oxidant and antioxidant play key role in the severity of sepsis. This article is protected by copyright. All rights reserved.
    Print ISSN: 0300-9475
    Electronic ISSN: 1365-3083
    Topics: Medicine
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  • 5
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    Publication Date: 2018-02-28
    Description: Modern diffusion magnetic resonance imaging (dMRI) acquires intricate volume datasets and biological meaning can only be found in the relationship between its different measurements. Suitable strategies for visualizing these complicated data have been key to interpretation by physicians and neuroscientists, for drawing conclusions on brain connectivity and for quality control. This article provides an overview of visualization solutions that have been proposed to date, ranging from basic grayscale and color encodings to glyph representations and renderings of fiber tractography. A particular focus is on ongoing and possible future developments in dMRI visualization, including comparative, uncertainty, interactive and dense visualizations. This paper provides an overview of visualization solutions that have been proposed to date for diffusion MRI, ranging from basic grayscale and color encodings to glyph representations and renderings of fiber tractography. A particular focus is on ongoing and possible future developments in dMRI visualization, including comparative, uncertainty, interactive, and dense visualizations.
    Print ISSN: 0952-3480
    Electronic ISSN: 1099-1492
    Topics: Medicine
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  • 6
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    Wiley-Blackwell
    Publication Date: 2018-03-06
    Description: Cover illustration. Additive manufacturing offers the capability to build reactors and components with complex geometries and topologies previously unaccessible to the reactor design engineer. These capabilities could allow a transition from site-built facilities [left, courtesy of Matt Jiggins, https://www.flickr.com/photos/mattjiggins/3948811131 ] to optimized additively manufactured designs [right, examples of metal objects built using Direct Metal Laser Sintering (DMLS) courtesy of Oakridge National Laboratory, https://www.flickr.com/photos/oakridgelab/9067742195 ]. 10.1002/aic.16118
    Print ISSN: 0001-1541
    Electronic ISSN: 1547-5905
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
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  • 7
    Publication Date: 2018-03-06
    Description: The cartwheel is a striking structure critical for building the centriole, a microtubule-based organelle fundamental for organizing centrosomes, cilia, and flagella. Over the last 50 years, the cartwheel has been described in many systems using electron microscopy, but the molecular nature of its constituent building blocks and their assembly mechanisms have long remained mysterious. Here, we review discoveries that led to the current understanding of cartwheel structure, assembly, and function. We focus on the key role of SAS-6 protein self-organization, both for building the signature ring-like structure with hub and spokes, as well as for their vertical stacking. The resemblance of assembly intermediates in vitro and in vivo leads us to propose a novel registration step in cartwheel biogenesis, whereby stacked SAS-6-containing rings are put in register through interactions with peripheral elements anchored to microtubules. We conclude by evoking some avenues for further uncovering cartwheel and centriole assembly mechanisms. The cartwheel is crucial for centriole assembly. Despite this fundamental role, cartwheel structure and assembly mechanisms remain unclear for a long time. Here we review five decades of research that led to our current understanding of these questions, highlighting the central role of the SAS-6 protein family.
    Print ISSN: 0265-9247
    Electronic ISSN: 1521-1878
    Topics: Biology , Medicine
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  • 8
    Publication Date: 2018-03-06
    Description: Despite the existence of well-established international environmental and nature conservation policies (e.g., the Ramsar Convention and Convention on Biological Diversity) ponds are largely missing from national and international legislation and policy frameworks. Ponds are among the most biodiverse and ecologically important freshwater habitats, and their value lies not only in individual ponds, but more importantly, in networks of ponds (pondscapes). Ponds make an important contribution to society through the ecosystem services they provide, with effective conservation of pondscapes essential to ensuring that these services are maintained. Implementation of current pond conservation through individual site designations does not function at the landscape scale, where ponds contribute most to biodiversity. Conservation and management of pondscapes should complement current national and international nature conservation and water policy/legislation, as pondscapes can provide species protection in landscapes where large-scale traditional conservation areas cannot be established (e.g., urban or agricultural landscapes). We propose practical steps for the effective incorporation or enhancement of ponds within five policy areas: through open water sustainable urban drainage systems in urban planning, increased incentives in agri-environment schemes, curriculum inclusion in education, emphasis on ecological scale in mitigation measures following anthropogenic developments, and the inclusion of pondscapes in conservation policy. This article is protected by copyright. All rights reserved
    Print ISSN: 1755-263X
    Electronic ISSN: 1755-263X
    Topics: Biology
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  • 9
    Publication Date: 2018-03-06
    Description: Several different assay methodologies have been described for the evaluation of HIV or SIV-specific antibody-dependent cell-mediated cytotoxicity (ADCC). Commonly used assays measure ADCC by evaluating effector cell functions, or by detecting elimination of target cells. Signaling through Fc receptors, cellular activation, cytotoxic granule exocytosis, or accumulation of cytolytic and immune signaling factors have been used to evaluate ADCC at the level of the effector cells. Alternatively, assays that measure killing or loss of target cells provide a direct assessment of the specific killing activity of antibodies capable of ADCC. Thus, each of these two distinct types of assays provides information on only one of the critical components of an ADCC event; either the effector cells involved, or the resulting effect on the target cell. We have developed a simple modification of our previously described high-throughput ADCC GranToxiLux (GTL) assay that uses area scaling analysis (ASA) to facilitate simultaneous quantification of ADCC activity at the target cell level, and assessment of the contribution of natural killer cells and monocytes to the total observed ADCC activity when whole human peripheral blood mononuclear cells are used as a source of effector cells. The modified analysis method requires no additional reagents and can, therefore, be easily included in prospective studies. Moreover, ASA can also often be applied to pre-existing ADCC-GTL datasets. Thus, incorporation of ASA to the ADCC-GTL assay provides an ancillary assessment of the ability of natural and vaccine-induced antibodies to recruit natural killer cells as well as monocytes against HIV or SIV; or to any other field of research for which this assay is applied. © 2018 International Society for Advancement of Cytometry
    Electronic ISSN: 1552-4930
    Topics: Biology , Medicine
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  • 10
    Publication Date: 2018-03-06
    Description: Flow cytometric cell surface proteomics provides a new and powerful tool to determine changes accompanying neoplastic transformation and invasion, providing clues to essential interactions with the microenvironment as well as leads for potential therapeutic targets. One of the most important advantages of flow cytometric cell surface proteomics is that it can be performed on living cells that can be sorted for further characterization and functional studies. Here, we document the surface proteome of clonogenic metastatic breast cancer (MBrCa) explants, which was strikingly similar to that of normal mesenchymal stromal cells ( P  = 0.017, associated with Pearson correlation coefficient) and transformed mammary epithelial cells ( P  = 0.022). Markers specifically upregulated on MBrCa included CD200 (Ox2), CD51/CD61 (Integrin α5/β3), CD26 (dipeptidyl peptidase-4), CD165 (c-Cbl), and CD54 (ICAM-1). Proteins progressively upregulated in a model of neoplastic transformation and invasion included CD26, CD63 (LAMP3), CD105 (Endoglin), CD107a (LAMP1), CD108 (Semaphorin 7A), CD109 (Integrin β4), CD151 (Raph blood group), and disialoganglioside G2. The proteome of the commonly used cell lines MDA-MB-231, MCF7, and BT-474 were uncorrelated with that of MBrCa ( P  = 1.0, 1.0, 0.9, respectively). The comparison has demonstrated the mesenchymal nature of clonogenic cells isolated by short-term culture of metastatic breast cancer, provided several leads for biomarkers and potential targets for anti-invasive therapy, including CD200, and highlighted the limitations of breast cancer cell lines for representing the cell surface biology of breast cancer. © 2017 International Society for Advancement of Cytometry
    Electronic ISSN: 1552-4930
    Topics: Biology , Medicine
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  • 11
    Publication Date: 2018-03-06
    Description: Implantation of micromass cultures of osteoblastic cells offers the possibility of scaffold free tissue engineering for example, regeneration of bone defects. However, the details of cell dynamics during the formation of these micromasses are still not well understood. This study aims to investigate and clarify the extent to which cell quantity influences the dynamics of micromass formation of osteoblastic cell cultures. For this purpose, the migration and aggregation during this process are investigated by optical inspection employing image processing software that allows for automated tracking of cell groups using digital image correlation. An exponential time behavior is observed with respect to the velocity of the cells and the distance of the cells to their common center of gravity. Characteristic time constants are derived as quantitative measures of the cell dynamics. The results indicate that the time constants strongly depend on the quantity of cells, that is, will decrease with increasing cell quantity. © 2018 International Society for Advancement of Cytometry Implantation of micromass cultures of osteoblastic cells offers the possibility of scaffold free tissue engineering for example, regeneration of bone defects. This study aims to clarify the extent to which cell quantity influences the dynamics of micro-mass formation of osteoblastic cell cultures. The migrations during these processes are investigated by optical inspection employing image processing software that allows for automated tracking of cell groups using digital image correlation (DIC).
    Electronic ISSN: 1552-4930
    Topics: Biology , Medicine
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  • 12
    Publication Date: 2018-03-06
    Description: Background : Traditionally, the central nervous system (CNS) has been viewed as an immune-privileged environment with no lymphatic vessels. This view was partially overturned by the discovery of lymphatic vessels in the dural membrane that surrounds the brain, in contact with the interior surface of the skull. We here examine the distribution and developmental timing of these lymphatic vessels. Results : Using the Prox1-GFP BAC transgenic reporter and immunostaining with antibodies to lymphatic markers LYVE-1, Prox1, and Podoplanin, we have carried out whole-mount imaging of dural lymphatic vasculature at postnatal stages. We have found that between birth – postnatal day 13 (P)13, lymphatic vessels extend alongside dural blood vessels from the side of the skull towards the midline. Between P13 - P20, lymphatic vessels along the transverse sinuses (TS) reach the superior sagittal sinus (SSS) and extend along the SSS towards the olfactory bulb. Conclusion : Compared with the embryonic developmental timing of lymphatic vessels in other tissues, e.g. skin, dural lymphatic vessel development is dramatically delayed. This study provides useful anatomical data for continuing investigations of the fundamental mechanisms that underlie dural lymphatic vessel development. This article is protected by copyright. All rights reserved.
    Electronic ISSN: 1097-0177
    Topics: Medicine
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  • 13
    Publication Date: 2018-03-06
    Description: Congenital HCMV infection is a leading infectious cause of long-term neurodevelopmental sequelae. Infection of newborn mice with MCMV intraperitoneally is a well-established model of congenital HCMV infection, which best recapitulates the hematogenous route of virus spread to brain and subsequent pathology. Here we used this model to investigate the role, dynamics and phenotype of CD8 + T cells in the brain following infection of newborn mice. We show that CD8 + T cells infiltrate the brain and form a pool of tissue-resident memory T cells (T RM cells) that persist for lifetime. Adoptively transferred virus-specific CD8 + T cells provide protection against primary MCMV infection in newborn mice, reduce brain pathology and remain in the brain as T RM cells. Brain CD8 + T RM cells were long-lived, slowly proliferating cells able to respond to local challenge infection. Importantly, brain CD8 + T RM cells controlled latent MCMV and their depletion resulted in virus reactivation and enhanced inflammation in brain. This article is protected by copyright. All rights reserved
    Print ISSN: 0014-2980
    Electronic ISSN: 1521-4141
    Topics: Medicine
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  • 14
    Publication Date: 2018-03-06
    Description: Although previous reports suggest that tumor-induced myeloid-derived suppressor cells (MDSC) inhibit T cells by L-arginine depletion through arginase-1 activity, we herein show that arginase-1 is neither inherently expressed in MDSC nor required for MDSC-mediated inhibition. Employing Percoll density gradients, large expansions of MDSC in the bone marrow of tumor-bearing mice were isolated and demonstrated potent inhibition in T cell proliferation activated by TCR-ligation, Concanavalin A, PMA plus ionomycin, or IL-2. Despite demonstrating characteristic immunosuppressive capacity, these MDSC exhibit no arginase-1 expression and/or exert their inhibitory effects independent of arginase-1 activity. However, arginase-1 expression in MDSC can be induced by exposure to TCR-activated T cells or their culture medium, but not T cells activated by other means or growing tumor cells. Further investigation reveals multiple cytokines secreted by TCR-activated T cells as orchestrating two signaling-relay axes, IL-6-to-IL-4 and GM-CSF/IL-4-to-IL-10, leading to arginase-1 expression in MDSC. Specifically, IL-6 signaling increases IL-4R, enabling IL-4 to induce arginase-1 expression; similarly, GM-CSF in concert with IL-4 induces IL-10R, allowing IL-10-mediated induction. Surprisingly, our study indicates that induction of arginase-1 expression is not conducive to the critical MDSC-mediated inhibition toward T cells, which is rather dependent on direct cell contacts undiminished by PD-L1 blockade or SIRPα deficiency. This article is protected by copyright. All rights reserved
    Print ISSN: 0014-2980
    Electronic ISSN: 1521-4141
    Topics: Medicine
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  • 15
    Publication Date: 2018-03-06
    Print ISSN: 0014-2980
    Electronic ISSN: 1521-4141
    Topics: Medicine
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  • 16
    Publication Date: 2018-03-06
    Description: Background Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with rising incidence. Biomarkers that would help the prognostic stratification of patients are urgently needed. Although tumour budding (BD) is a strong and independent prognostic factor in PDAC, is not included in histopathology reports, partly due to lack of standardized scoring system. Aim Aim of the present work is to assess the reliability and reproducibility of the BD scoring system recently proposed by the International Tumour Budding Concensus Conference (ITBCC) 2016, in a well-characterized PDAC-cohort (n=120) with complete clinico-pathological and follow-up information. Methods BD was scored independently by two pathologists on H&E-stained PDAC-sections by assessing the densest budding area at 20x-magnification (one “hotspot”, 0.785mm 2 ) regardless of intra-or peritumoural localisation and assigned into four categories: BD0: 0 buds; BD1: 1-4 buds; BD2: 5-9 buds; and BD3: ≥10 buds. Findings were correlated to patient and tumour characteristics und inter-observer agreement was assessed. Results Weighted kappa value for BD-category was 0.62 (0.5-0.73) indicating strong agreement. Increasing BD-category (BD3 versus BD0-2) correlated with higher grade (p=0.002) and shorter overall (OS, p〈0.0001; HR(95%CI)=3.234(1.95-5.37)) and disease-free survival (DFS, p=0.0135; HR(95%CI)=1.974(1.15-3.39)). BD (BD3 versus BD0-2) was an independent prognostic factor for OS and DFS, after adjusting for TNM-stage by using both the 8 th AJCC Edition (OS; p=0.0031;HR(95%CI)=2.298(1.32-.99)); (DFS; p=0.0458;HR(95%CI)=1.713(1.01-2.91)) and the 7 th AJCC Edition (OS; p〈0.0001;HR(95%CI)=2.795(1.71-4.57)) and (DFS; p=0.00786;HR(95%CI)=1.643(0.95-2.86)). Conclusions ITBCC-scoring is a simple, reliable and reproducible method to evaluate BD in PDAC and facilitates its documentation in histopathology reports allowing the prognostic stratification of PDAC-patients. This article is protected by copyright. All rights reserved.
    Print ISSN: 0309-0167
    Electronic ISSN: 1365-2559
    Topics: Medicine
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  • 17
    Publication Date: 2018-03-06
    Description: Aims Extraskeletal osteosarcoma (ESOS) is a sarcoma in the non-skeletal tissue that directly produces neoplastic osteoid or bone. Dedifferentiated liposarcoma (DDLPS) and malignant peripheral nerve sheath tumor (MPNST) are the two most common types of sarcoma that can harbor heterologous osteosarcomatous differentiation. We aimed to determine the potential relationship of ESOS to DDLPS and MPNST. Methods and results We investigated MDM2 and H3K27me3 status in 19 cases of ESOS, 2 of which contained a low-grade component. The ESOSs affected deep soft tissues (n=10), superficial soft tissues (n=3), and organs (n=6). Among 10 deep soft-tissue ESOSs, 6 showed MDM2 amplification, 4 of which also harbored CDK4 co-amplification. Both ESOSs with a low-grade component showed co-amplification for MDM2 and CDK4 . Among the 6 organ-based ESOSs, 3 giant cell-rich ESOSs showed an H3K27me3 deficiency (1 in primary and 2 in metastatic sites). Using targeted next generation sequencing, an H3K27me3-deficient ESOS showed EED homozygous deletion, while none of the 3 showed alterations in NF1 , CDKN2A , or SUZ12 genes. During median follow-up of 20 months, all 6 patients with MDM2 -amplified ESOS lived for 3–103 months, while 2 of the 3 patients with H3K27me3-deficient ESOS died from this disease in 4 and 20 months, respectively. Conclusion We demonstrate that ESOS may include at least two small subsets: an MDM2 -amplified deep soft-tissue ESOS (which may be related to DDLPS) and an H3K27me3-deficient organ-based ESOS (which is probably unrelated to MPNST). Larger studies are required to validate the present observations and investigate the clinical implications of such subcategorization. This article is protected by copyright. All rights reserved.
    Print ISSN: 0309-0167
    Electronic ISSN: 1365-2559
    Topics: Medicine
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  • 18
    Publication Date: 2018-03-06
    Description: Pulmonary Sarcomatoid Carcinoma (PSC) is a poorly-differentiated non-small cell lung carcinoma (NSCLC) with aggressive behavior. This study aimed to evaluate the prognostic clinicopathologic and genetic characteristics of PSCs. Fifty-three cases of surgically treated PSCs were selected, of which 23 were subjected to mutation and copy number variation analysis using 50-gene Ion AmpliSeq Cancer Panel. Majority of the patients were male (32/53, 60.3%) and smoker (51/53, 96.2%). Overall, 25 (47.1%) patients died within 2 to 105 months (mean 22.7 months, median 15 months) after diagnosis, and 28 were alive as of 3 to 141 months (mean 38.7 months, median 21.5 months) after diagnosis. Five-year overall survival was 12.5%. KRAS codon 12/13 mutation in adenocarcinomas (p= 0.01), age over 70 years (p=0.008) and tumor size ≥ 4.0 cm (p= 0.02) were strongly associated with worse outcome. TP53 (17/23, 74.0%) and KRAS  codon 12/13 mutations (10/23, 43.4%) were the most common genetic alterations. Potentially actionable variants were identified including ATM (4/23, 17.3%), MET, FBXW7 and EGFR (2/23, 8.7%) , AKT1, KIT, PDGFRA, HRAS, JAK3 , and SMAD4 (1/23, 4.3%). MET exon 14 skipping and missense mutations were identified in two (11.1%) cases with adenocarcinoma histology. Copy number analysis showed loss of RB1 (3/23, 13%) and ATM (2/23, 8.7%). Copy number gains were seen in EGFR (2/23, 13.0%), and in one (4.3%) of each PIK3CA , KRAS, MET , and STK11 . Potentially targetable mutations can be identified in a subset of PSC although most tumors harbor currently untargetable prognostically adverse TP53 and KRAS mutations. This article is protected by copyright. All rights reserved.
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    Electronic ISSN: 1365-2559
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  • 19
    Publication Date: 2018-03-06
    Description: Aims To establish whether core needle biopsy (CNB) specimens processed with an accelerated processing method with short fixation time can be used to accurately determine HER2 status of breast cancer. Methods and results A consecutive case series from two high volume breast clinics was created. We compared routine HER2 immunohistochemistry (IHC) assessment between accelerated processing CNB specimens and routinely processed postoperative excision specimens. Additional amplification-based testing was performed in cases with equivocal results. The formalin fixation time was less than 2 hours and between 6 and 72 hours, respectively. Fluorescent in situ hybridization and multiplex ligation-dependent probe amplification were used for amplification testing. One hundred and forty-four cases were included, 15 of which were HER2 positive on the routinely processed excision specimens. On the CNB specimens, 44 were equivocal on IHC and required an amplification-based test. Correlation between the CNB specimens and the corresponding excision specimens was high for final HER2 status, with an accuracy of 97% and a kappa of 0.85. Conclusions HER2 status can be reliably determined on CNB specimens with accelerated processing time using standard clinical testing methods. Using this accelerated technology, the minimum six hours of formalin fixation which current guidelines consider necessary, can safely be decreased. This allows for a complete and expedited histology-based diagnosis of breast lesions in the setting of a one-stop-shop, same-day breast clinic. This article is protected by copyright. All rights reserved.
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    Electronic ISSN: 1365-2559
    Topics: Medicine
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  • 20
    Publication Date: 2018-03-06
    Description: Introduction The tumor microenvironment is increasingly important in several tumors. We studied the relationship of key players of immune microenvironment with clinicopathological parameters in gastric adenocarcinomas. Methods Tissue microarrays were constructed from gastrectomy specimens, 2004-2013. Immunohistochemistry was performed for programmed death ligand 1 (PD-L1), indoleamine 2,3-dioxygenase (IDO), tryptophanyl-tRNA synthetase (WARS), guanylate-binding protein 5 (GBP5), tumor-infiltrating lymphocytes (TIL) expressing CD3/CD8/FoxP3/PD1, and mismatch repair proteins (MMRs) MLH1, PMS2, MSH2 and MSH6. Clinicopathological parameters and clinical follow-up were recorded. Results The study included 86 patients, median follow-up was 34 months (0-148). Tumor types were 45% tubular, 38% diffuse, 17% mixed. PD-L1 was positive in 70%, epithelial IDO in 58%, stromal IDO in 91%, epithelial WARS in 67%, stromal WARS in 100%, epithelial GBP5 in 53%, and stromal GBP5 in 71%. MMR-deficiency was found in 22%. There was no difference in biomarker expression by histological subtype, with exception fewer diffuse-type being MMR-deficient. Low stromal IDO was associated with decreased progression-free, overall and disease-specific survival. PD-L1-positive tumors were larger with MMR-deficiency and with increasing TILs, and had significantly higher FoxP3- TILs. Conclusions PD-L1 is expressed in a large proportion of gastric carcinomas suggesting that therapy targeting this pathway could be relevant to many patients. PD-L1 expression and MMR-deficiency are associated with increased TILs and larger tumor size, emphasizing their role in tumor biology. Higher stromal IDO expression is associated with better prognosis. Finally, we observed that immune modulators WARS and GBP5 are highly expressed in gastric adenocarcinomas, suggesting an important role in tumor pathobiology. This article is protected by copyright. All rights reserved.
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    Topics: Medicine
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  • 21
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    Publication Date: 2018-03-06
    Print ISSN: 0019-2805
    Electronic ISSN: 1365-2567
    Topics: Medicine
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  • 22
    Publication Date: 2018-03-06
    Description: Salivary duct carcinoma (SDC) is a subtype of salivary gland cancer with a dismal prognosis and a need for better prognostication and novel treatments. The aim of this national cohort study was to investigate clinical outcome, prognostic factors, Androgen Receptor (AR) and Human Epidermal Growth Factor Receptor 2 (HER2) expression. SDC patients diagnosed between 1990 – 2014 were identified by the Nationwide Network and Registry of Histo- and Cytopathology in the Netherlands (PALGA). Subsequently, medical records were evaluated and pathological diagnoses reviewed. Data were analyzed for overall survival (OS), disease free survival (DFS), distant metastasis free survival (DMFS), and prognostic factors. AR was evaluated by immunohistochemistry (IHC), HER2 by IHC and fluorescent-in-situ-hybridization. A total of 177 patients were included. The median age was 65 years, 75% were male. At diagnosis, 68% presented with lymph node metastases and 6% with distant metastases. Median OS, DFS and DMFS were 51, 23 and 26 months, respectively. In patients presenting without distant metastases, the absolute number of positive lymph nodes was associated with poor OS and DMFS in a multivariable analysis. AR and HER2 were positive in 161/168 (96%) and 44/153 (29%) tumors, respectively, and were not prognostic factors. SDC has a dismal prognosis with primary lymph node involvement in the majority of patients. The absolute number of lymph node metastases was found to be the only prognostic factor for DMFS and OS. AR expression and, to a lesser extent, HER2 expression hold promise for systemic treatment in the metastatic and eventually adjuvant setting. This article is protected by copyright. All rights reserved.
    Print ISSN: 0020-7136
    Electronic ISSN: 1097-0215
    Topics: Biology , Medicine
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  • 23
    Publication Date: 2018-03-06
    Description: Obesity has been postulated to increase the risk of colorectal cancer by mechanisms involving insulin resistance and the metabolic syndrome. We examined the associations of body mass index (BMI), waist circumference, the metabolic syndrome, metabolic obesity phenotypes, and homeostasis model-insulin resistance (HOMA-IR – a marker of insulin resistance) with risk of colorectal cancer in over 21,000 women in the Women's Health Initiative CVD Biomarkers subcohort. Women were cross-classified by BMI (18.5-〈25.0, 25.0-〈30.0, and ≥30.0 kg/m 2 ) and presence of the metabolic syndrome into 6 phenotypes: metabolically healthy normal weight (MHNW), metabolically unhealthy normal weight (MUNW), metabolically healthy overweight (MHOW), metabolically unhealthy overweight (MUOW), metabolically healthy obese (MHO), and metabolically unhealthy obese (MUO). Neither BMI nor presence of the metabolic syndrome was associated with risk of colorectal cancer, whereas waist circumference showed a robust positive association. Relative to the MHNW phenotype, the MUNW phenotype was associated with increased risk, whereas no other phenotype showed an association. Furthermore, HOMA-IR was not associated with increased risk. Overall, our results do not support a direct role of metabolic dysregulation in the development of colorectal cancer; however, they do suggest that higher waist circumference is a risk factor, possibly reflecting the effects of increased levels of cytokines and hormones in visceral abdominal fat on colorectal carcinogenesis. This article is protected by copyright. All rights reserved.
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    Electronic ISSN: 1097-0215
    Topics: Biology , Medicine
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  • 24
    Publication Date: 2018-03-06
    Description: The role of host epigenetic mechanisms in the natural history of low-grade cervical intraepithelial neoplasia (CIN1) is not well characterized. We explored differential methylation of imprinted gene regulatory regions as predictors of the risk of CIN1 regression. A total of 164 patients with CIN1 were recruited from 10 Duke University clinics for the CIN Cohort Study. Participants had colposcopies at enrollment and up to five follow-up visits over three years. DNA was extracted from exfoliated cervical cells for methylation quantitation at CpG (cytosine-phosphate-guanine) sites and human papillomavirus (HPV) genotyping. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression to quantify the effect of methylation on CIN1 regression over two consecutive visits, compared to non-regression (persistent CIN1; progression to CIN2+; or CIN1 regression at a single time-point), adjusting for age, race, high-risk HPV (hrHPV), parity, oral contraceptive and smoking status. Median participant age was 26.6 years (range: 21-64.4 years), 39.0% were African-American, and 11% were current smokers. Most participants were hrHPV-positive at enrollment (80.5%). Over one-third of cases regressed (n=53, 35.1%). Median time-to-regression was 12.6 months (range: 4.5-24.0 months). Probability of CIN1 regression was negatively correlated to methylation at IGF2AS CpG 5 (HR=0.41; 95% CI=0.23-0.77) and PEG10 DMR (HR=0.80; 95% CI=0.65-0.98). Altered methylation of imprinted IGF2AS and PEG10 DMRs may play a role in the natural history of CIN1. If confirmed in larger studies, further research on imprinted gene DMR methylation is warranted to determine its efficacy as a biomarker for cervical cancer screening. This article is protected by copyright. All rights reserved.
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    Electronic ISSN: 1097-0215
    Topics: Biology , Medicine
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  • 25
    Publication Date: 2018-03-06
    Description: Background Glioma cells may infiltrate beyond the tumor margins revealed on conventional structural images. Purpose To investigate whether the presence of a glioma infiltration sign on high b-value diffusion-weighted imaging (DWI) can predict the prognosis of gliomas. Study Type Retrospective cohort. Subjects Fifty-two patients with gliomas (14 WHO grade II; 13 WHO grade III; 25 WHO grade IV). Field Strength/Sequence 3.0T, including a T 1 -weighted contrast-enhanced (T 1 w-CE) sequence, contrast-enhanced T 2 -flair sequence, and a DWI sequence. Assessment T 1 w-CE images and contrast-enhanced T 2 -flair images were used for identifying the tumor region for enhancing and nonenhancing gliomas, respectively. The glioma infiltration sign was defined as the presence of a peritumoral abnormal high signal region on DWI map, which was adjacent to the tumor region and had higher signal than surrounding areas. This sign was assessed on a high b-value DWI map with b  = 3000 s/mm 2 . For patients with glioma infiltration sign, DWI3000 max , DWI1000 max , ADC3000 min , and ADC1000 min were measured by drawing a region of interest over the peritumoral abnormal high signal region. Statistical Tests Survival analysis was conducted by using Cox regression. Results Glioma infiltration sign was observed in 28 (53.8%) patients. The occurrence rate of this sign was 92.0% in grade IV gliomas, 30.8% in grade III gliomas, and 7.1% in grade II gliomas. The glioma infiltration sign could independently predict both the progression-free survival (hazard ratio [HR], 95% confidence interval [CI] = 8.58 [3.19–23.03], P  〈 0.001) and overall survival (HR, 95% CI = 11.90 [3.41–41.55], P  〈 0.001) after adjustment. For patients with glioma infiltration sign, DWI3000 max ( P  = 0.005) and ADC3000 min ( P  = 0.008) were both independent predictors of overall survival after adjustment, while DWI1000 max and ADC1000 min were not. Data Conclusion The glioma infiltration sign on high b-value DWI is an independent predictor of poor prognosis in glioma patients. High b-value DWI might be a convenient method to detect glioma infiltration. Level of Evidence: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018.
    Print ISSN: 1053-1807
    Electronic ISSN: 1522-2586
    Topics: Medicine
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  • 26
    Publication Date: 2018-03-06
    Description: One of the therapeutic options for the treatment of fulminant hepatitis is re-population of intrahepatic regulatory cells since their pool is significantly reduced during acute liver failure. Although it is known that mesenchymal stem cells (MSCs), which have beneficent effects in the therapy of fulminant hepatitis, may promote expansion of T regulatory cells (Tregs) and B regulatory cells (Bregs), the role of these regulatory cells in MSC-mediated attenuation of acute liver injury is unknown. Herewith, we described the molecular mechanisms involved in the crosstalk between MSCs and liver regulatory cells and analyzed the potential of MSC-based therapy for the expansion of intrahepatic regulatory cells in mouse model of acute liver failure. MSC-dependent attenuation of α-galactosylceramide (α-GalCer)-induced acute liver injury in mice was accompanied with an increased presence of IL-10 producing CD4 + CD25 + FoxP3 + Tregs and IL-10 and TGF-β producing marginal zone (MZ)-like Bregs in the liver. Depletion of Bregs did not alter MSC-based alleviation of acute liver failure, while depletion of Tregs completely abrogated hepato-protective effects of MSCs and inhibit their capacity to attenuate hepatotoxicity of liver natural killer T (NKT) cells, indicating that Tregs, and not Bregs, were critically involved in MSC-based modulation of acute liver inflammation. MSCs, in paracrine, indoleamine 2,3-dioxygenase (IDO)-dependent manner, significantly increased capacity of Tregs to produce immunosuppressive IL-10 and to suppress hepatotoxicity of liver NKT cells. Accordingly, adoptive transfer of MSC-primed Tregs resulted with the complete attenuation of α-GalCer-induced acute liver failure. In conclusion, our findings highlighted the crucial importance of Tregs for MSC-based attenuation of acute liver failure and indicate the significance of MSC-mediated priming of Tregs as new therapeutic approach in Tregs-based therapy of acute liver injury. This article is protected by copyright. All rights reserved.
    Print ISSN: 1527-6465
    Electronic ISSN: 1527-6473
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  • 27
    Publication Date: 2018-03-06
    Print ISSN: 1527-6465
    Electronic ISSN: 1527-6473
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  • 28
    Publication Date: 2018-03-06
    Description: ABSTRACT Background : Although the type of hepatic artery revascularization technique is known to impact on patency rates, independent perioperative risk factors on patient outcomes are poorly defined. Methods : All consecutive adult patients undergoing cadaveric liver transplantation (n=361) from July 2007 to June 2016 in a single institution were analyzed. Primary outcomes were early (〈30 days) hepatic artery occlusion and primary hepatic artery patency rate. A multivariate model was used to identify independent risk factors for occlusion and the need of arterial conduit, as well as their impact on graft and patient survival. Results : Arterial revascularization without additional reconstruction (AA) was performed in 77% (n=279), arterial reconstruction (AR) in 15% (n=53), and aorto-hepatic conduit (AHC) in 8% (n=29) of cases, respectively. AHC had the highest mean intraoperative flow (275 ml/min; p=0.024) compared to AA (250 ml/min) and AR (200 ml/min), p=0.024. 43 recipients (12%) had an occlusive event with successful revascularization in 20 recipients (47%). One-year primary patency rates of AA, AR, and AHC were 97, 88, and 74%. Aortic calcification had an impact on early occlusion. AR (OR 3.68 (1.26-10.75), p=0.017) and AHC (OR 6.21 (2.02-18.87, p=0.001) were independent risk factors for early occlusion. Dyslipidemia additionally independently contributed to early occlusion (OR 2.74 (0.96-7.87), p=0.06). One- and five-year graft survival were 83% and 70% for AA, 75% and 69% for AR, and 59% and 50% for AHC (p=0.004). Conclusions : Arterial patency is primarily determined by the type of vascular reconstruction rather than patient or disease characteristics. The preoperative lipid status is an independent risk factor for early occlusion, while overall occlusion is only based on the performed vascular reconstruction, which is also associated with reduced graft and patient survival. This article is protected by copyright. All rights reserved.
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  • 29
    Publication Date: 2018-03-06
    Description: We investigated the adhesive behaviour of mesenchymal stem cells (MSC) in blood, which might influence their fate when infused as therapy. Isolated human bone marrow (BM) or umbilical cord (UC) MSC adhered efficiently from flow to the matrix proteins, collagen or fibronectin, but did not adhere to endothelial selectins. However, when suspended in blood, BMMSC no longer adhered to collagen, while UCMSC adhered along with many aggregated platelets. Neither MSC adhered to fibronectin from flowing blood, although the fibronectin surface did become coated with a platelet monolayer. UCMSC induced platelet aggregation in platelet rich plasma, and caused a marked drop in platelet count when mixed with whole human or mouse blood in vitro, or when infused into mice. In contrast, BMMSC did not activate platelets or induce changes in platelet count. Interestingly, isolated UCMSC and BMMSC both adhered to pre-deposited platelets. The differences in behaviour in blood were attributable to expression of podoplanin (an activating ligand for the platelet receptor CLEC-2), which was detected on UCMSC, but not BMMSC. Thus, platelets were activated when bound to UCMSC, but not BMMSC. Platelet aggregation by UCMSC was inhibited by recombinant soluble CLEC-2, and UCMSC did not cause a reduction in platelet count when mixed with blood from mice deficient in CLEC-2. We predict that both MSC would carry platelets in the blood, but their interaction with vascular endothelium would depend on podoplanin-induced activation of the bound platelets. Such interactions with platelets might target MSC to damaged tissue, but could also be thrombotic. This article is protected by copyright. All rights reserved. BMMSC and UCMSC are both able to bind directly to collagen and fibronectin. However, in blood, BMMSC bind platelets which are inactive and effectively shield them so that they do not adhere to platelets deposited on fibronectin or collagen. UCMSC express podoplanin (PDPN) so that they not only bind platelets but also activated them through CLEC-2. They bind with activated platelets on collagen but do not adhere to the minimally activated platelets on fibronectin. In the flowing blood, the UCMSC with bound platelets may be able to drive wider-spread activation and aggregation of platelets, that leads to a reduction in platelet count in vitro or in vivo.
    Print ISSN: 1066-5099
    Electronic ISSN: 1549-4918
    Topics: Medicine
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  • 30
    Publication Date: 2018-03-07
    Description: Despite their diversity and ecological importance, many areas of the SAR—Stramenopila, Alveolata, and Rhizaria—clade are poorly understood as the majority (90%) of SAR species lack molecular data and only 5% of species are from well-sampled families. Here, we review and summarize the state of knowledge about the three major clades of SAR, describing the diversity within each clade and identifying synapomorphies when possible. We also assess the “dark area” of SAR: the morphologically described species that are missing molecular data. The majority of molecular data for SAR lineages are characterized from marine samples and vertebrate hosts, highlighting the need for additional research effort in areas such as freshwater and terrestrial habitats and “non-vertebrate” hosts. We also describe the paucity of data on the biogeography of SAR species, and point to opportunities to illuminate diversity in this major eukaryotic clade. See also the video abstract here: https://youtu.be/_VUXqaX19Rw . Despite their diversity, abundance, and importance, fewer than 10% of the species within the SAR—Stramenopila, Alveolata, and Rhizaria—clade have been assessed using molecular tools. Only a small percentage of the molecular records contain information on ecology or have associate location data, indicating a tremendous dark area.
    Print ISSN: 0265-9247
    Electronic ISSN: 1521-1878
    Topics: Biology , Medicine
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  • 31
    Publication Date: 2018-03-07
    Description: The present study aimed to evaluate the efficacy of cabazitaxel in Japanese patients affected by metastatic castration resistant prostate cancer (mCRPC) previously treated with a docetaxel-containing regimen.In this retrospective study, 41 patients with mCRPC treated with cabazitaxel at Keio University Hospital were retrospectively reviewed. Cabazitaxel at a dose of 20-25 mg/m² was administered every three or four weeks. Clinicopathological factors and laboratory data were collected to assess the prognostic factors for overall survival (OS) and progression-free survival (PFS).An upfront dose-reduction was required in 52.5% of patients due to their reduced general condition or advanced age. Prophylactic G-CSF was prescribed to all the patients. Grade ≥3 neutropenia and Febrile neutropenia occurred in 21 patients and (53.6%) and 3 patients (6.8%), respectively. Treatment was generally well tolerated with a median of 5 cycles (range 1-17). Median PFS and OS from the start of cabazitaxel treatment were 4.4 months and 15.0 months (95% CI 8.9– 21.2), respectively. Waterfall plot analysis revealed a PSA decline 〉 50% was noticed in n=11 patients receiving cabazitaxel (26.8%).Univariate analysis revealed that an poor performance status, PSA ≥100 ng/mL prior to cabazitaxel treatment, visceral metastasis, the absence of grade 3/4 neutropenia during cabazitaxel therapy and NLR were significantly associated with shorter overall survival. Multivariate analysis revealed that poor PS, visceral metastasis, and the absence of grade 3/4 neutropenia during cabazitaxel therapy were the independent prognostic indicators for OS. The practical implication of our results might be to tailor cabazitaxel dosing on the basis of its haematological effects. This article is protected by copyright. All rights reserved.
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  • 32
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    Wiley-Blackwell
    Publication Date: 2018-03-07
    Description: Cover of this issue. Cladogran of taxa of microbiota in the mice in the model and Bifico group. See also Song et al. (pp. 666–677 of this issue).
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  • 33
    Publication Date: 2018-03-07
    Description: Despite considerable research on K-Ras inhibitors, none had been developed until now. We synthesized nuclease-resistant synthetic miR-143 (miR-143#12), which strongly silenced K-Ras, its effector signal molecules AKT and ERKs, and the K-Ras activator Sos1. We examined the anti-proliferative effect of miR-143#12 and the mechanism in human colon cancer DLD-1 cell (G13D) and other cell types harboring K-Ras mutations. Cell growth was markedly suppressed in a concentration-dependent manner by miR-143#12 (IC 50 : 1.32 nM) with a decreased in the K-Ras mRNA level. Interestingly, this mRNA level was also down-regulated by either a PI3K/AKT or MEK inhibitor, which finding indicates a positive circuit of K-Ras mRNA expression. MiR-143#12 silenced cytoplasmic K-Ras mRNA expression and impaired the positive circuit by directly targeting AKT and ERK mRNAs. Combination treatment with miR-143#12 and a low-dose EGFR inhibitor induced a synergistic inhibition of growth with a marked inactivation of both PI3K/AKT and MAPK/ERK signaling pathways. However, silencing K-Ras by siR-KRas instead of miR-143#12 did not induce this synergism by the combined treatment with the EGFR inhibitor. Thus, miR-143#12 perturbed the K-Ras expression system and K-Ras activation by silencing Sos1 and resultantly, recovered the efficacy of the EGFR inhibitors. In vivo results also supported those of the in vitro experiments. The extremely potent miR-143#12 enabled us to well understand K-Ras signaling networks and shut them down by combination treatment with this miRNA and EGFR inhibitor in K-Ras-driven colon cancer cell lines. This article is protected by copyright. All rights reserved.
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  • 34
    Publication Date: 2018-03-07
    Description: In boron neutron capture therapy (BNCT), 10 B-4-borono-L-phenylalanine (BPA) is commonly used as a 10 B carrier. Positron emission tomography using 4-borono-2- 18 F-fluoro-phenylalanine ( 18 F-FBPA PET) has been performed to estimate boron concentration and predict the therapeutic effects of BNCT; however, the association between tumor uptake of 18 F-FBPA and boron concentration in tumors remains unclear. The present study investigated the transport mechanism of 18 F-FBPA and BPA, and evaluated the utility of 18 F-FBPA PET in predicting boron concentration in tumors. The transporter assay revealed that 2-aminobicyclo-(2.2.1)-heptane-2-carboxylic acid, an inhibitor of the L-type amino acid transporter, significantly inhibited 18 F-FBPA and 14 C-BPA uptake in FaDu and LN-229 human cancer cells. 18 F-FBPA uptake strongly correlated with 14 C-BPA uptake in seven human tumor cell lines (r = 0.93; p 〈0.01). PET experiments demonstrated that tumor uptake of 18 F-FBPA was independent of the administration method, and uptake of 18 F-FBPA by bolus injection correlated well with BPA uptake by continuous intravenous infusion. The results of this study revealed that evaluating tumor uptake of 18 F-FBPA by PET was useful for estimating 10 B concentration in tumors. This article is protected by copyright. All rights reserved.
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  • 35
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    Wiley-Blackwell
    Publication Date: 2018-03-07
    Print ISSN: 0007-9235
    Electronic ISSN: 1542-4863
    Topics: Medicine
    Published by Wiley-Blackwell on behalf of American Cancer Society.
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  • 36
    Publication Date: 2018-03-07
    Description: Nivolumab belongs to the standard therapy in the second-line setting of metastatic renal cell carcinoma (mRCC). Although deep and long-lasting responses are seen in some patients, the majority of patients will further progress. PD-L1 as predictive biomarker is still under critical evaluation. Thus, more accurate biomarkers are clearly warranted. Here, we investigated for the first time the predictive role of IDO-1, a negative immune-regulatory molecule, on clear cell RCC tissues of 15 patients undergoing nivolumab therapy. IDO-1 and other immune inhibitory molecules (PD-L1, PD-L2, FOXP3) as well as immune cell subsets (CD3, CD4, CD8) were measured on formalin-fixed, paraffin-embedded sections of RCC specimens by immunohistochemistry. IDO-1 was predominantly expressed in tumor endothelial cells, and was totally absent from tumor cells itself. IDO-1 overexpression (〉10%) could be detected more frequently in responders (100%, n=6/6) compared to non-responders (33.3%, n=3/9; p =0.028), resulting in a better progression-free survival during immunotherapy (IDO-1 ≤10% vs . 〉10%, median: 3.5 vs . NE months, p =0.01 by log-rank test). In addition, IDO-1 was positively correlated with CD8 + T cell expression (r s =0.691, p =0.006). PD-L1 expression on tumor cells was negative in 13 (86.7%) of 15 patients, irrespective of therapeutic response (responders vs . non-responders: 83.3% vs . 88.9%). No differences were noticed in the PD-L1 expression on tumor-infiltrating immune cells (PD-L1〈1% in 66.7% of both responders and non-responders). In contrast to PD-L1, these results suggest that IDO-1 may be a more promising predictive biomarker for response to immune-based cancer therapy in mRCC. This article is protected by copyright. All rights reserved.
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  • 37
    Publication Date: 2018-03-07
    Description: Metastasis is the leading cause of cancer deaths. A tumor-supportive microenvironment, or premetastatic niche, at potential secondary tumor sites plays an important role in metastasis, especially in tumor cell colonization. Although a fibrotic milieu is known to promote tumorigenesis and metastasis, the underlying molecular contributors to this effect have remained unclear. Here we show that periostin, a component of the extracellular matrix that functions in tissue remodeling, has a key role in formation of a fibrotic environment that promotes tumor metastatic colonization. We found that periostin was widely expressed in fibrotic lesions of mice with bleomycin-induced lung fibrosis, and that up-regulation of periostin expression coincided with activation of myofibroblasts positive for α–smooth muscle actin. We established a lung metastasis model for B16 murine melanoma cells and showed that metastatic colonization of the lung by these cells was markedly promoted by bleomycin-induced lung fibrosis. Inhibition of periostin expression by intratracheal administration of an antisense oligonucleotide targeting periostin mRNA was found to suppress bleomycin-induced lung fibrosis and thereby to attenuate metastatic colonization of the lung by melanoma cells. Our results indicate that periostin is a key player in the development of bleomycin-induced fibrosis and consequent enhancement of tumor cell colonization in the lung, and they therefore implicate periostin as a potential target for prevention or treatment of lung metastasis. This article is protected by copyright. All rights reserved.
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  • 38
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    Publication Date: 2018-03-07
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  • 39
    Publication Date: 2018-03-07
    Description: Angioimmunoblastic T-cell lymphoma (AITL) is a subtype of nodal peripheral T-cell lymphomas. Somatic RHOA mutations, most frequently found at the hotspot site c.50G〉T, p. Gly17Val (G17V RHOA mutation) are a genetic hallmark of AITL. Detection of the G17V RHOA mutations assists prompt and appropriate diagnosis of AITL. However, an optimal detection method for the G17V RHOA mutation remains to be elucidated. We compared the sensitivity and concordance of next generation sequencing (NGS), droplet digital PCR (ddPCR) and PNA-LNA clamp method for detecting the G17V RHOA mutations. The G17V RHOA mutations were identified in 27 of 67 (40.3%) PTCL samples using NGS. ddPCR and PNA-LNA clamp method both detected the G17V mutations in 4 samples in addition to those detected with NGS (31of 67, 46.3%). Additionally, variant allele frequencies with ddPCR and those with NGS showed high concordance ( P 〈0.001). Three other RHOA mutations involving the p.Gly17 position (c.[49G〉T;50G〉T], p.Gly17Leu in PTCL198; c.[50G〉T;51A〉C], p.Gly17Val in PTCL216; and c.50G〉A, p.Gly17Glu in PTCL223) were detected using NGS. These sequence changes could not appropriately be detected using the ddPCR assay and PNA-LNA clamp method although both indicated that the samples might have mutations. In total, 34 out of 67 PTCL samples (50.7%) had the RHOA mutations at the p.Gly17Val position. In conclusion, our results suggested that combination of ddPCR/PNA-LNA clamp methods and NGS are best feasible to assist the diagnosis of AITL by detecting the RHOA mutations at the p.Gly17 position. This article is protected by copyright. All rights reserved.
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  • 40
    Publication Date: 2018-03-07
    Description: Natural killer (NK) cells express an array of germ-line encoded receptors that are capable of triggering cytotoxicity. NK cells tend to express many members of a given family of signaling molecules. The presence of many activating receptors and many members of a given family of signaling molecules can enable NK cells to detect different kinds of target cells, and to mount different kinds of responses. This contributes also to the robustness of NK cells responses; cytotoxic functions of NK cells often remain unaffected in the absence of selected signaling molecules. NK cells express many MHC-I-specific inhibitory receptors. Signals from MHC-I-specific inhibitory receptors tightly control NK cell cytotoxicity and, paradoxically, maintain NK cells in a state of proper responsiveness. This review provides a brief overview of the events that underlie NK cell activation, and how signals from inhibitory receptors intercept NK cell activation to prevent inappropriate triggering of cytotoxicity. This article is protected by copyright. All rights reserved.
    Print ISSN: 0019-2805
    Electronic ISSN: 1365-2567
    Topics: Medicine
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  • 41
    Publication Date: 2018-03-07
    Description: A number of polymorphisms in immune-regulatory genes have been identified as risk factors for the development of autoimmune disease. PTPN22 , that encodes a tyrosine phosphatase, has been associated with the development of several autoimmune diseases including type 1 diabetes, rheumatoid arthritis and systemic lupus erythematosus. PTPN22 regulates the activity and effector functions of multiple important immune cell types including lymphocytes, granulocytes and myeloid cells. In this review, we describe the role of PTPN22 in regulating T cell activation and effector responses. We discuss progress in our understanding of the impact of PTPN22 in autoimmune disease in humans and mouse models as well as recent evidence suggesting that genetic manipulation of PTPN22 expression might enhance the efficacy of anti-tumour T cell responses. This article is protected by copyright. All rights reserved.
    Print ISSN: 0019-2805
    Electronic ISSN: 1365-2567
    Topics: Medicine
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  • 42
    Publication Date: 2018-03-07
    Description: Background Protective roles have been proposed for vitamin D in prostate cancer, which has the advanced age as the major risk factor. However, little is known about the expression of the vitamin D receptor (VDR) in the aging prostate and its association with the development of epithelial lesions that affect tissue homeostasis and may precede prostate tumors. Methods VDR expression in the prostatic complex of young adults to senile Wistar rats, a natural model to study age-related prostatic disorders, was evaluated by immunohistochemical, Western blotting, and image-assisted analyzes. Results were correlated with the plasma levels of vitamin D and testosterone, the occurrence of punctual histopathological changes in the aging prostate, and the expression of retinoid X receptors (RXR). Results VDR was widely distributed in the prostatic complex at all ages analyzed, with the highest immunoexpression found in basal epithelial cells. As the animals aged, VDR levels increased, except in punctual areas with intraepithelial proliferation, metaplasia, or proliferative inflammatory atrophy, which had reduced expression of this receptor concomitantly with increased cell proliferation. Interestingly, RXR expression in the aging prostate was similar to that found for its partner VDR, indicating that components of the VDR/RXR complex required for vitamin D signaling are affected in aging-related prostatic lesions. Moreover, plasma vitamin D levels declined at the same ages when prostatic alterations appeared. Although circulating levels of testosterone also decreased with aging, the changes observed in the components of the vitamin D system were not correlated with androgens. Conclusions Our data indicate that the aging prostate suffers from an imbalance on the intricate mechanism of tissue regulation by the vitamin D responsive system. We argue that the status of VDR expression might be determinant for the development of histopathological alterations in the aging prostate, which include premalignant lesions.
    Print ISSN: 0270-4137
    Electronic ISSN: 1097-0045
    Topics: Medicine
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  • 43
    Publication Date: 2018-03-07
    Description: Terrestrial primary production is a fundamental ecological process and a crucial component in understanding the flow of energy through trophic levels. The global MODIS gross primary production (GPP) and net primary production (NPP) products (MOD17) are widely used for monitoring GPP and NPP at coarse resolutions across broad spatial extents. The coarse input datasets and global biome-level parameters, however, are well-known limitations to the applicability of the MOD17 product at finer scales. We addressed these limitations and created two improved products for the conterminous United States (CONUS) that capture the spatiotemporal variability in terrestrial production. The MOD17 algorithm was utilized with medium resolution land cover classifications and improved meteorological data specific to CONUS in order to produce: (a) Landsat derived 16-day GPP and annual NPP at 30 m resolution from 1986 to 2016 (GPP L 30 and NPP L 30 , respectively); and (b) MODIS derived 8-day GPP and annual NPP at 250 m resolution from 2001 to 2016 (GPP M 250 and NPP M 250 respectively). Biome-specific input parameters were optimized based on eddy covariance flux tower-derived GPP data from the FLUXNET2015 database. We evaluated GPP L 30 and GPP M 250 products against the standard MODIS GPP product utilizing a select subset of representative flux tower sites, and found improvement across all land cover classes except croplands. We also found consistent interannual variability and trends across NPP L 30 , NPP M 250 , and the standard MODIS NPP product. We highlight the application potential of the production products, demonstrating their improved capacity for monitoring terrestrial production at higher levels of spatial detail across broad spatiotemporal scales. We produced two higher resolution primary production datasets, using better input data than currently existing datasets. These products more closely match the scale of many ecological processes and management activities, and will facilitate better understandings of production dynamics. Our products correspond well with other production datasets at multiple scales. The products fill a critical gap in our ability to monitor and assess terrestrial production dynamics in relation to many ecological processes and land use change. As production is a foundational ecological process and ecosystem service, understanding these dynamics is critical for environmental sustainability.
    Electronic ISSN: 2056-3485
    Topics: Architecture, Civil Engineering, Surveying , Biology
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  • 44
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    Wiley-Blackwell
    Publication Date: 2018-03-07
    Print ISSN: 1066-5099
    Electronic ISSN: 1549-4918
    Topics: Medicine
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  • 45
    Publication Date: 2018-03-09
    Description: The Gram-negative outer membrane (OM) is a potent permeability barrier against antibiotics, limiting clinical options amid mounting rates of resistance. The Lol transport pathway delivers lipoproteins to the OM. All the OM assembly machines require one or more OM lipoprotein to function, making the Lol pathway central for all aspects of OM biogenesis. The Lol pathways of many medically important species clearly deviate from the Escherichia coli paradigm, perhaps with implications for efforts to develop novel antibiotics. Moreover, recent work reveals the existence of an undiscovered alternate route for bringing lipoproteins to the OM. Here, lipoprotein transport mechanisms, and the quality control systems that underpin them, is re-examined in context of their diversity. All essential outer membrane assembly machines (Bam, Lpt, and Lol) require lipoproteins to function. Hence, the transport mechanisms supplying these lipoproteins are critical for maintaining the integrity of the outer membrane barrier against antibiotics. Lipoprotein transport strategies of diverse Gram-negative bacteria will be reviewed in the context of recent discoveries.
    Print ISSN: 0265-9247
    Electronic ISSN: 1521-1878
    Topics: Biology , Medicine
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  • 46
    Publication Date: 2018-03-09
    Print ISSN: 1015-6305
    Electronic ISSN: 1750-3639
    Topics: Medicine
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  • 47
    Publication Date: 2018-03-09
    Print ISSN: 1015-6305
    Electronic ISSN: 1750-3639
    Topics: Medicine
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  • 48
    Publication Date: 2018-03-09
    Description: ABSTRACT Down syndrome (DS) is a genetic condition associated with impairment in several cognitive domains. Previous evidence showed a notable neurogenesis reduction in the hippocampal region of DS fetuses, which may account for the impairment of declarative memory that characterizes DS starting from early life stages. The fusiform gyrus (FG) and the inferior temporal gyrus (ITG) play a key role in visual recognition memory, a function that is impaired in children and adults with DS. The goal of the current study was to establish whether fetuses with DS (17-21 weeks of gestation) exhibit neuroanatomical alterations in the FG and ITG that may underlie recognition memory impairment. We found that the FG and ITG of fetuses with DS had a reduced thickness and fewer cells in comparison with euploid fetuses. Moreover, DS fetuses had fewer cells expressing the neuronal marker NeuN than euploid fetuses, but a similar number of cells expressing the astrocytic marker GFAP and, consequently, a higher percentage of astrocytes. Immunohistochemistry for calretinin (CR), a marker of GABAergic interneurons, showed that in DS fetuses the ratio of CR-positive versus CR-negative cells was greater than in euploid fetuses, both in the FG (+77%) and ITG (+61%). An increased ratio of CR-positive versus CR-negative cells was also found in the entorhinal cortex, hippocampus and dentate gyrus. Results provide novel evidence that the FG and ITG of DS fetuses exhibit numerous developmental defects. These defects may underlie the functional alterations in visual recognition memory observed in children with DS. This article is protected by copyright. All rights reserved.
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  • 49
    Publication Date: 2018-03-09
    Print ISSN: 1015-6305
    Electronic ISSN: 1750-3639
    Topics: Medicine
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  • 50
    Publication Date: 2018-03-09
    Description: Background Interleukin-31 (IL-31) is implicated in pruritus associated with pruritic skin diseases like atopic dermatitis. Although pruritus is a prominent feature in dermatomyositis (DM), few studies have evaluated the pathogenesis of DM-associated itch. Objectives Our goals were to establish the prevalence of itch in DM, and to investigate the role of IL-31 in DM-related itch. Methods Pruritus and disease activity of DM were evaluated by a visual analog scale (VAS) and the Cutaneous Disease and Activity Severity Index (CDASI), respectively. Expression of IL-31 and IL-31 receptor alpha (IL-31RA) in lesional DM, non-lesional DM and healthy control (HC) skin was evaluated by qRT-PCR and immunofluorescence. Flow cytometry was performed on skin cells isolated from lesional DM skin to identify cellular sources of IL-31 in DM. Results Among 191 DM patients, 50.8% had moderate to severe itch, and itch was correlated with increased cutaneous severity (r= 0.34). In itchy DM patients, gene expression of IL-31 and IL-31RA in lesional skin was upregulated compared to non-lesional skin and HC skin. IL-31 mRNA expression positively correlated with VAS itch score (r= 0.67). On immunofluorescence, immunoreactivity for IL-31 and IL31RA was stronger in lesional skin. Flow cytometry showed lesional DM skin contained significantly more IL-31-producing cells and CD4+ cells were the most common cell type. Lenabasum, an emerging treatment for DM, significantly downregulated IL-31 from CpG-stimulated PBMCs. Conclusion Increased skin IL-31 may play a role in DM-associated itch, and ongoing trials will evaluate the effects of systemic treatment on IL-31 and itch in DM. This article is protected by copyright. All rights reserved.
    Print ISSN: 0007-0963
    Electronic ISSN: 1365-2133
    Topics: Medicine
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  • 51
    Publication Date: 2018-03-09
    Description: Treatment for patients with V600 mutation of the B-Raf protooncogene BRAF (BRAF-V600) and metastatic stage IV or unresectable stage III melanoma has greatly advanced with the introduction of selective BRAF inhibitors (BRAFi), such as vemurafenib and dabrafenib, combined with mitogen-activated protein kinase kinase inhibitors (MEKi), such as cobimetinib and trametinib, as first-line therapy [1,2]. Two mutations, V600E and V600K, are routinely searched in patients with stage IV and unresectable stage III cancer. The presence of the V600 mutation allows for prescribing BRAFi combined with MEKi according to the European Medicine Agency. Other non– BRAF-V600 mutations have been increasingly found by next-generation sequencing (NGS) and question the possible efficiency of BRAFi associated with MEKi with these mutations [3]. Here we report a case of metastatic melanoma in a patient with a non–BRAF-V600 mutation responding to combined BRAFi and MEKi treatment. This article is protected by copyright. All rights reserved.
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    Electronic ISSN: 1365-2133
    Topics: Medicine
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  • 52
    Publication Date: 2018-03-09
    Description: Palmoplantar keratodermas (PPKs, OMIM #144200) refers to a large phenotypically and genetically heterogeneous group of keratinization disorders characterized by marked hyperkeratosis on the surface of palms and soles. Punctate PPK (PPKP) features multiple hyperkeratotic papules that develop in early adolescence or later and are irregularly distributed on the palms and soles. The disease is clinically classified into three autosomal dominant subtypes: PPKP1 (OMIM #148600, 614936) characterized by multiple tiny punctate keratoses and caused by mutations in the AAGAB or COL14A1 genes; PPKP2 (OMIM #175860) which features tiny hyperkeratotic spinous papules and PPKP3 or acrokeratoelastoidosis (AKE, OMIM # 101850) which manifests with small hyperkeratotic papules located over the peripheral margins of the palms and soles and is typically associated with degeneration of elastic fibers on histology. The molecular etiology of PPKP2 and AKE remains unknown. This article is protected by copyright. All rights reserved.
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    Electronic ISSN: 1365-2133
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  • 53
    Publication Date: 2018-03-09
    Description: BACKGROUND To the authors' knowledge, social network status in adolescent and young adult (AYA) cancer survivors has not been adequately studied to date. The authors developed and validated a functional social network index (FSNI) for AYA survivors, and compared its performance with that of 2 traditional indices (density and betweenness centrality). METHODS A total of 102 AYA survivors and 102 noncancer controls who were matched for age, sex, and race were recruited from an Internet panel. Each participant reported relationships with up to 25 close friends and/or relatives. The authors developed a FSNI with reported marital status, contact frequency with friends/relatives, available resources for emotional and tangible support, and available resources for physical activity and weight management advice. Linear regression was used to analyze associations between the FSNI and cancer diagnoses, treatments, and coping skills. RESULTS Based on the FSNI, survivors were found to have more available resources for emotional support (beta [b] = 3.02; P = .003), tangible support (b = 4.17; P 〈.001), physical activity advice (b = 3.94; P 〈.001), and weight management advice (b = 4.10; P 〈.001) compared with noncancer controls. Survivors of lymphoma had the largest FSNI, whereas survivors of central nervous system malignancies had the smallest (b = 2.77; P = .02). A higher FSNI was associated with better coping skills: less denial (b = 0.10; P = .01), using emotional support (b = 0.08; P = .04), using instrumental support (b = 0.12; P 〈.001), less behavioral disengagement (b = 0.08; P = .04), venting of emotions (b = 0.10; P = .004), positive reframing (b = 0.12; P = .003), planning for the future (b = 0.08; P = .03), and religious engagement (b = 0.16; P 〈.001). Density and betweenness centrality indices demonstrated neither significant differences in social networks between cancer survivors and controls (all P values 〉.05) nor significant associations with coping skills (all P values 〉.05). CONCLUSIONS The FSNI appears to provide a better social network assessment for AYA cancer survivors than traditional indices. Cancer 2018 . © 2018 American Cancer Society .
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    Electronic ISSN: 1097-0142
    Topics: Biology , Medicine
    Published by Wiley-Blackwell on behalf of The American Cancer Society.
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  • 54
    Publication Date: 2018-03-09
    Description: BACKGROUND To explore the clinical efficacy of traditional herbal medicine (THM) in the prevention of disease recurrence of small hepatocellular carcinoma after surgery, a prospective randomized controlled study was conducted between October 2006 and May 2010. The results indicated that THM prevented the recurrence of SHCC with an efficacy that was superior to that of transarterial chemoembolization (TACE) during a median follow-up of 26.61 months. METHODS The patients were followed up every 6 months, and the clinical data before October 20, 2015 were analyzed. The primary outcome measure was recurrence-free survival (RFS), and the secondary outcome measure was overall survival (OS). RESULTS The 364 patients included 180 in the THM group and 184 in the TACE group. At the time of the data cutoff of October 20, 2015, a total of 205 patients demonstrated disease recurrence, including 85 patients in the THM group and 120 patients in the TACE group. The median RFS of the THM and TACE groups demonstrated a statistically significant difference ( P 〈.001). Until October 20, 2105, there were 91 deaths, including 34 in the THM group and 57 in the TACE group. The median OS demonstrated a significant difference between the 2 groups ( P =  .008). Multivariate analysis indicated that THM was an independent factor influencing RFS and OS. CONCLUSIONS The efficacy of THM was found to be superior to that of TACE in preventing disease recurrence in patients with small hepatocellular carcinoma and prolonging OS. Cancer 2018. © 2018 American Cancer Society .
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    Electronic ISSN: 1097-0142
    Topics: Biology , Medicine
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  • 55
    Publication Date: 2018-03-09
    Description: BACKGROUND To the authors' knowledge, the survival benefit of local therapy in the setting of advanced prostate cancer remains unknown. The authors investigated whether prostate-directed treatment with either surgery or radiotherapy versus conservative treatment in the setting of locally advanced or metastatic disease was associated with improved survival within a cohort of men from the Centers for Disease Control and Prevention's (CDC) Breast and Prostate Cancer Data Quality and Patterns of Care Study (CDC POC-BP). METHODS Men diagnosed with locally advanced (cT3-T4 or N+ and M0) or metastatic prostate cancer were identified. The authors compared survival by treatment type, categorized as conservative (androgen deprivation therapy only) versus aggressive (radical prostatectomy or any type of radiotherapy). Nine-year overall survival and prostate cancer-specific survival were estimated using the Kaplan-Meier method. The Cox proportional hazards model was used to determine factors independently associated with 9-year prostate cancer-specific survival. RESULTS For men with advanced, nonmetastatic prostate cancer, conservative treatment alone was associated with a 4 times higher likelihood of prostate cancer mortality compared with men treated with surgery (hazard ratio, 4.18; 95% confidence interval, 1.44-12.14). In contrast, no difference was found between conservative versus aggressive treatment after adjusting for covariates for men with metastatic disease. The 9-year prostate cancer-specific survival rate was 27% for those receiving aggressive treatment versus 24% for men undergoing conservative treatment. CONCLUSIONS The authors did not observe a survival advantage with local therapy in addition to standard androgen deprivation therapy for men with metastatic prostate cancer. However, the results of the current study did affirm advantages in the setting of locally advanced disease. Aggressive local therapy in the setting of metastatic disease needs to be studied carefully before clinical adoption. Cancer 2018 . © 2018 American Cancer Society .
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    Topics: Biology , Medicine
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  • 56
    Publication Date: 2018-03-09
    Description: This study investigated the association of nutritional and haematological variables with maximum time-averaged mean velocity (TAMV) measured by transcranial Doppler (TCD) velocity and the agreement of classification between two protocols. TCD categories included: normal (〈170 cm/s), conditional (170–199 cm/s) and abnormal (≥200 cm/s) based on TAMV in distal internal carotid artery (dICA), middle cerebral artery (MCA), internal carotid bifurcation, anterior and posterior cerebral arteries. Of 358 children with sickle cell anaemia (SCA) examined, the mean age (±standard deviation) was 7·4 ± 2·7 years; 13·1% and 6·7% had conditional and abnormal velocities, respectively. Children with abnormal TCD velocities had higher prevalence of prior stroke ( P  = 0·006). Increased TAMV was associated with younger age ( P  = 0·001), lower weight ( P  = 0·001), height ( P  = 0·007) and oxygen saturation ( P  = 0·005). There was no association of TAMV with height-age or body mass index (BMI) z -scores. Adjusting for gender, BMI z -score, age, previous stroke and oxygen saturation, mean corpuscular volume ( P  = 0·005) and reticulocyte count ( P  = 0·013) were positively associated with TAMV, while haemoglobin concentration ( P  = 0·009) was negatively associated. There was good agreement [99%; weighted Kappa 0·98 (95% confidence interval 0·89–1), P  = 0·0001] in TCD classification using data from five vessels versus two vessels (dICA and MCA). Haematological variables, rather than nutritional status, may be useful markers that identify high-risk children with SCA.
    Print ISSN: 0007-1048
    Electronic ISSN: 1365-2141
    Topics: Medicine
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  • 57
    Publication Date: 2018-03-09
    Description: BACKGROUND Inotuzumab ozogamicin (InO), an anti-CD22 antibody-calicheamicin conjugate, demonstrated superior clinical activity versus standard-of-care (SOC) chemotherapies for relapsed/refractory B-cell acute lymphoblastic leukemia in the phase 3 randomized controlled INO-VATE trial. The authors assessed patient-reported outcomes (PROs) from that study. METHODS Patients were randomized to receive either InO (1.8 mg/m 2 per cycle for ≤6 cycles) or SOC (fludarabine/cytarabine [ara-C]/granulocyte colony-stimulating factor, or ara-C plus mitoxantrone, or high-dose ara-C for ≤4 cycles) and completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and the EuroQoL 5 Dimensions Questionnaires at baseline, on day 1 of each cycle, and at the end of treatment. Treatment differences in PROs were assessed using longitudinal mixed-effects models with random intercepts and slopes. RESULTS Questionnaire completion rates in the InO (n = 164) and SOC (n = 162) arms were 85% and 65%, respectively. Baseline scores were similar between arms. Patients who received InO reported better quality of life (QoL), functioning, and symptom scores (except for constipation and emotional functioning). Least-squares mean (95% confidence interval [CI]) differences in physical, role, and social functioning and in appetite loss were significant (6.9 [95% CI, 1.4-12.3], 11.4 [95% CI, 3.2-19.5], 8.4 [95% CI, 0.7-16.1], and −8.7 [95% CI, −16.0 to −1.4], respectively; all P 〈 .05) and had exceeded the minimally important difference of 5. Mean treatment differences in favor of InO on the EuroQoL visual analog scale and the global health status/QoL, dyspnea, and fatigue scales reached or approached the minimally important difference of 5, although without statistical significance. No dimensions were significantly worse with InO versus SOC. CONCLUSIONS The current PRO data support the favorable benefit/risk ratio of InO for the treatment of relapsed/refractory acute lymphoblastic leukemia, with superior clinical efficacy and better QoL. Cancer 2018 . © 2018 American Cancer Society .
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    Electronic ISSN: 1097-0142
    Topics: Biology , Medicine
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  • 58
    Publication Date: 2018-03-09
    Description: BACKGROUND The National Cancer Institute's cancer incidence estimates through 2015 from the Surveillance, Epidemiology, and End Results (SEER) registries' November 2017 submission are released in April 2018. METHODS Early estimates (February 2017) of cancer incidence rates and trends from the SEER 18 registries for diagnoses in 2000 through 2015 were evaluated with a revised delay-adjustment model, which was used to adjust for the undercount of cases in the early release. For the first time, early estimates were produced for race (whites and blacks) along with estimates for new sites: the oral cavity and pharynx, leukemia, and myeloma. RESULTS Model validation comparing delay-adjusted rates and trends through 2014 and using 2016 submissions showed good agreement. Differences in trends through 2015 in comparison with those through 2014 were evident. The rate of female breast cancer rose significantly from 2004 to 2015 by 0.3% per year (annual percent change [APC] = 0.3%); the prior trend through 2014 (the same magnitude) was not yet significant. The female colon and rectum cancer trend for whites became flat after previously declining. Lung and bronchus cancer for whites showed a significant decline (APC for males = −2.3%, 2012-2015; APC for females = −0.7%, 2011-2015). Thyroid cancer for black females changed from a continuous rise to a flat final segment (APC = 1.6%, not significant, 2011-2015). Both kidney and renal pelvis cancer (APC = 1.5%, 2011-2015) and childhood cancers (APC = 0.5%, 2000-2015) for white males showed a significant rise in the final segments from previously flat trends. Kidney and renal pelvis cancer for black males showed a change from a significant rise to a flat trend. CONCLUSIONS The early release of SEER data continues to be useful as a preliminary estimate of the most current cancer incidence trends. Cancer 2018 . © 2018 American Cancer Society .
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    Electronic ISSN: 1097-0142
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  • 59
    Publication Date: 2018-03-09
    Description: Background Biologics used increasingly used for treating moderate-to-severe psoriasis. Efficacy may differ in patients with previous biologics exposure. Objective To investigate the impact of previous biologic exposure on efficacy and safety of brodalumab and ustekinumab in moderate-to-severe plaque psoriasis. Methods Two placebo- and ustekinumab-controlled phase 3 clinical trials. Initial 12-week induction phase where patients were treated with brodalumab (210mg Q2W or 140mg Q2W), ustekinumab or placebo. Efficacy endpoints included: Psoriasis Area and Severity Index (PASI 75) and Physician's Global Assessment (sPGA 0/1) versus placebo, PASI 100 versus ustekinumab, Dermatology Life Quality Index (DLQI) and Psoriasis Symptom Inventory (PSI). Adverse events were monitored throughout. Results 493 patients (334 [27%] brodalumab 210 mg Q2W and 159 [26%] ustekinumab) received prior biologics exposure; 150 (12%) and 62 (10%) reporting previously failed biologic. Brodalumab efficacy in patients with or without previous biologics exposure was statistically equivalent; 40.9% and 39.5% of bio-naïve and -experienced patients achieved PASI 100 at Week 12, compared with 21.1% and 17.0% with ustekinumab (both P〈0.001). In patients where prior biologics had been successful or failed, 41.7% and 32.0% achieved PASI 100, compared with 21.1% and 11.3% with ustekinumab. Tolerability was similar, and did not appear to be influenced by previous biologic treatment. Conclusions Efficacy of brodalumab 210 mg Q2W was similar regardless of prior biologic therapy (P=0.31, 0.32 and 0.64 for PASI 75, 90, and 100 respectively). Almost twice as many patients achieved PASI 100 or complete clearance at Week 12 compared with ustekinumab; differences most noticeable where previous biologics had failed. Both treatments were well tolerated. This article is protected by copyright. All rights reserved.
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    Electronic ISSN: 1365-2133
    Topics: Medicine
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  • 60
    Publication Date: 2018-03-09
    Description: BACKGROUND Biomarker-guided clinical trials are increasingly common in metastatic urothelial carcinoma (mUC), yet patients for whom contemporary tumor tissue is not available are not eligible. Technological advancements in sequencing have made cell-free circulating DNA (cfDNA) next-generation sequencing (NGS) readily available in the clinic. The objective of the current study was to determine whether the genomic profile of mUC detected by NGS of cfDNA is similar to historical tumor tissue NGS studies. A secondary objective was to determine whether the frequency of genomic alterations (GAs) differed between lower tract mUC (mLTUC) and upper tract mUC (mUTUC). METHODS Patients from 13 academic medical centers in the United States who had a diagnosis of mUC between 2014 and 2017 and for whom cfDNA NGS results were available were included. cfDNA profiling was performed using a commercially available platform (Guardant360) targeting 73 genes. RESULTS Of 369 patients with mUC, 294 were diagnosed with mLTUC and 75 with mUTUC. A total of 2130 GAs were identified in the overall mUC cohort: 1610 and 520, respectively, in the mLTUC and mUTUC cohorts. In the mLTUC cohort, frequently observed GAs were similar between cfDNA NGS and historical tumor tissue studies, including tumor protein p53 ( TP53 ) ( P = 1.000 and .115, respectively), AT-rich interaction domain 1A ( ARID1A ) ( P = .058 and .058, respectively), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha ( PIK3CA ) ( P = .058 and .067, respectively), erb-b2 receptor tyrosine kinase 2 ( ERBB2 ) ( P = .565 and .074, respectively), and fibroblast growth factor receptor 3 ( FGFR3 ) ( P = .164 and .014, respectively). No significant difference was observed with regard to the frequency of GAs between patients with mLTUC and mUTUC. CONCLUSIONS Among patients with mUC for whom no tumor tissue was available, cfDNA NGS was able to identify a similar profile of GAs for biomarker-driven clinical trials compared with tumor tissue. Despite the more aggressive clinical course, cases of mUTUC demonstrated a circulating tumor DNA genomic landscape that was similar to that of mLTUC. Cancer 2018 . © 2018 American Cancer Society .
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  • 61
    Publication Date: 2018-03-09
    Description: Cancer pain remains a feared consequence of the disease and its treatment. Although prevalent, cancer pain can usually be managed through the skillful application of pharmacologic and nonpharmacologic interventions. Unfortunately, access to these therapies has been hampered by interventions designed to contain another serious public health problem: the opioid misuse epidemic. This epidemic and the unintended consequences of efforts to control this outbreak are leading to significant barriers to the provision of cancer pain relief. Oncologists and other professionals treating those with cancer pain will require new knowledge and tools to provide safe and effective pain control while preventing additional cases of substance use disorders (SUDs), helping patients in recovery to maintain sobriety, and guiding those not yet in recovery to seek treatment. How do these 2 serious epidemics intersect and affect oncology practice? First, oncology professionals will need to adopt practices to prevent SUDs by assessing risk and providing safe pain care. Second, oncology practices are likely to see an increased number of patients with a current or past SUD, including opioid misuse. Few guidelines exist for the direct management of pain when opioids may be indicated in these individuals. Third, modified prescribing practices along with the education of patients and families are warranted to prevent the exposure of these medications to unintended persons. Finally, advocacy on behalf of those with cancer pain is imperative to avoid losing access to essential therapies, including opioids, for those who might benefit. Cancer 2018 . © 2018 American Cancer Society .
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  • 62
    Publication Date: 2018-03-09
    Description: BACKGROUND The objective of this study was to prospectively evaluate dose-intensified hypofractionated stereotactic body radiation therapy (SBRT) in patients with painful spinal metastases in a multicenter, single-arm, phase 2 study. METHODS Patients with 2 or fewer distinct, noncontiguous, painful, mechanically stable, unirradiated spinal metastases from a solid tumor with a Karnofsky performance status ≥ 60 were eligible. Patients with a long (Mizumoto score ≤ 4) or intermediate overall survival expectancy (Mizumoto score = 5-9) received 48.5 Gy in 10 fractions or 35 Gy in 5 fractions, respectively, with SBRT. The primary outcome was the overall (complete and partial) pain response as measured with international consensus guidelines 3 months after SBRT. RESULTS There were 57 patients enrolled between 2012 and 2015, and 54 of these patients with 60 painful vertebral metastases were analyzed. The 3-month pain response was evaluated in 42 patients (47 lesions). An overall pain response was observed in 41 lesions (87%), and the pain response remained stable for at least 12 months. The mean maximum pain scores on a visual analogue scale significantly improved from the baseline of 6.1 (standard deviation, 2.5) to 2.0 (standard deviation, 2.3) 3 months after treatment ( P 〈 .001). The 5-level EuroQol 5-Dimension Questionnaire quality-of-life (QOL) dimensions (self-reported mobility, usual activities, and pain/discomfort) significantly improved from the baseline to 3 months after treatment. The 12-month overall survival and local control rates were 61.4% (95% confidence interval [CI], 48%-74.8%) and 85.9% (95% CI, 76.7%-95%), respectively. Grade 3 toxicity was limited to acute pain in 1 patient (2%). No patient experienced radiation-induced myelopathy. Six patients (11%) developed progressive vertebral compression fractures (VCFs), and 8 patients (15%) developed new VCFs. CONCLUSIONS Dose-intensified SBRT achieved durable local metastasis control and resulted in pronounced and long-term pain responses and improved QOL. Cancer 2018 . © 2018 American Cancer Society .
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  • 63
    Publication Date: 2018-03-09
    Description: BACKGROUND Although breast cancer often is perceived to be indolent in older women, breast cancer outcomes in the oldest patients are variable. In the current study, the authors examined breast cancer-specific death by age, stage, and disease subtype in a large, population-based cohort. METHODS Using Surveillance, Epidemiology, and End Results data, a total of 486,118 women diagnosed with American Joint Committee on Cancer stage I to IV breast cancer between 2000 and 2012 were identified. Using a series of Fine and Gray regression models to account for competing risk, the authors examined the risk of breast cancer-specific death by age and stage (I-IV) for subcohorts with hormone receptor (HR)-positive, HR-negative, human epidermal growth factor receptor 2-positive, and triple-negative disease, adjusting for demographic and clinical variables. RESULTS Overall, 18% of women were aged 65 to 74 years, 13% were aged 75 to 84 years, and 4% were aged ≥85 years. Regardless of stage of disease within the HR-positive and HR-negative cohorts, patients aged ≥75 years (vs those aged 55-64 years) experienced a higher adjusted hazard of breast cancer-specific death, which was particularly evident for those with early-stage, HR-positive disease (hazard ratio for those aged 75-84 years, 1.88 [95% confidence interval, 1.68-2.09] and hazard ratio for those aged ≥85 years, 3.59 [95% confidence interval, 3.12-4.13] [both for stage I disease]). In the cohorts with human epidermal growth factor receptor 2-positive and triple-negative disease, women aged ≥70 years had a consistently higher risk of breast cancer-specific death across disease stages (vs those aged 51-60 years), with the exception of stage IV triple-negative disease. CONCLUSIONS Older patients experience worse breast cancer outcomes, regardless of disease subtype and stage. With an increasing number of older patients anticipated to develop breast cancer in the future, addressing disparities for older patients must emerge as a clinical and research priority. 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.
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  • 64
    Publication Date: 2018-03-09
    Description: In this report, we describe the circularly polarized luminescence (CPL) of the RNA duplexes having one to four 2′-O-pyrene modified uridines ( Upy ) and the DNA duplexes having two, four, and six pyrene modified non-nucleosidic linkers ( Py ). Both the pyrene π-stack arrays formed on the RNA and DNA double helical structures exhibited pyrene excimer fluorescence. In the pyrene-modified RNA systems, the RNA duplex having four Upy s gives CPL emission with g lum value of 〈0.01 at 480 nm. The structure of pyrene stacks on the RNA duplex may be rigidly regulated with increase in the Upy domains, which resulted in the CPL emission. In the DNA systems, the pyrene-modified duplexes containing two and four Pys exhibited CPL emission with g lum values of 〈0.001 at 505 nm. The pyrene π-stack arrays presented here show CPL emission. However, the g lum values are relatively small when compared with our previous system consisting of the pyrene-zipper arrays on RNA.
    Print ISSN: 0899-0042
    Electronic ISSN: 1520-636X
    Topics: Chemistry and Pharmacology
    Published by Wiley-Blackwell
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  • 65
    Publication Date: 2018-03-09
    Description: The management of conflicts between wildlife conservation and agricultural practices often involves the implementation of strategies aimed at reducing the cost of wildlife impacts on crops. Vital to the success of these strategies is the perception that changes in management efforts are synchronised relative to changes in impact levels, yet this expectation is never evaluated. We assess the level of synchrony between time series of population counts and management effort in the context of conflicts between agriculture and five populations of large grazing birds in northern Europe. We reveal inconsistent patterns of synchrony and asynchrony between changes in population counts and impact management effort relating to population harvesting, monetary payments or scaring practices. This variation is likely due to differing management aims, the existence of lags between management decisions and population monitoring, and the inconsistent use of predictive models across case studies. Overall, our findings highlight the need for more adaptive and timely responses of management to changes in target species numbers so as not to unexpectedly increase social conflicts and jeopardise the status of wildlife populations. This article is protected by copyright. All rights reserved
    Print ISSN: 1755-263X
    Electronic ISSN: 1755-263X
    Topics: Biology
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  • 66
    Publication Date: 2018-03-09
    Description: Genomic studies have been used to identify genes underlying many important plant secondary metabolic pathways. However, genes for salicinoid phenolic glycosides (SPGs)—ecologically important compounds with significant commercial, cultural, and medicinal applications—remain largely undescribed. We used a linkage map derived from a full-sib population of hybrid cottonwoods ( Populus spp.) to search for quantitative trait loci (QTL) for the SPGs salicortin and HCH-salicortin. SSR markers and primer sequences were used to anchor the map to the V3.0 P. trichocarpa genome. We discovered 21 QTL for the two traits, including a major QTL for HCH-salicortin ( R 2  = .52) that colocated with a QTL for salicortin on chr12. Using the V3.0 Populus genome sequence, we identified 2,983 annotated genes and 1,480 genes of unknown function within our QTL intervals. We note ten candidate genes of interest, including a BAHD-type acyltransferase that has been potentially linked to Populus SPGs. Our results complement other recent studies in Populus with implications for gene discovery and the evolution of defensive chemistry in a model genus. To our knowledge, this is the first study to use a full-sib mapping population to identify QTL intervals and gene lists associated with SPGs. Salicinoid phenolic glycosides (SPGs) are important secondary metabolites with numerous ecological, commercial, and ethnobotanical applications. However, the pathways controlling the expression of SPGs remain conspicuously underscribed. Here, discuss 25 quantitative trait loci (QTL) associated with the salicinoid phenolic gylcosides, salicortin and HCH-salicortin, and a number of potential candidate genes that occur within our QTL intervals.
    Electronic ISSN: 2045-7758
    Topics: Biology
    Published by Wiley-Blackwell
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  • 67
    Publication Date: 2018-03-09
    Description: Unexpected fetal loss is one of the common complications of pregnancy; however, the pathogenesis of many miscarriages, particularly those not associated with infections, is unknown. We previously found that activated DEC-205 + dendritic cells (DCs) and NK1.1 + invariant natural killer T (iNKT) cells are recruited into the myometrium of mice when miscarriage is induced by the intraperitoneal administration of α-galactosylceramide (α-GalCer). Here we demonstrate that the adoptive transfer of DEC-205 + bone marrow-derived DCs cocultured with α-GalCer (DEC-205 + BMDCs-c/w-α-GalCer) directly induced marked fetal loss by syngeneic pregnant C57BL/6 (B6) mice and allogeneic mice (B6 (♀) × BALB/c (♂)), which was accompanied by the accumulation of activated iNKT cells in the myometrium. Further, the adoptive transfer of NK1.1 + iNKT cells obtained from B6 mice injected with α-GalCer facilitated miscarriages in syngeneic Jα18(-/-) (iNKT cell-deficient) mice. These results suggest that DEC-205 + DCs and NK1.1 + iNKT cells play crucial roles required for the initiation of fetal loss associated with stimulation by glycolipid antigens and sterile inflammation. This article is protected by copyright. All rights reserved
    Print ISSN: 0014-2980
    Electronic ISSN: 1521-4141
    Topics: Medicine
    Published by Wiley-Blackwell
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  • 68
    Publication Date: 2018-03-09
    Description: Aims Most gastric carcinomas develop in association with mucosal atrophy and hypochlorhydria, whereas benign peptic ulcers are acid-related. Given that acid sterilizes gastric contents, we hypothesized that ulcerated gastric cancers may be associated with increased luminal microbes compared with peptic ulcers, and that this feature may represent a helpful diagnostic clue to the presence of malignancy. We performed this study to determine whether features of luminal debris, including microorganisms, from ulcerated gastric cancers were significantly different from those of debris associated with benign ulcers. Methods and Results We retrospectively identified 50 ulcerated adenocarcinomas and 50 site-matched peptic ulcers. Luminal debris was evaluated for nature of inflammation, necrosis, and presence of mixed bacterial colonies or yeast. Non-lesional mucosa was assessed for chronic gastritis, Helicobacter pylori , chemical gastropathy, and intestinal metaplasia. Patients in both groups were adults (mean age: 69 and 62 years, respectively) with similar amounts of inflammation and cellular necrosis in biopsy material. However, 76% of ulcerated cancers harbored non- H.pylori bacterial colonies, compared with only 22% of peptic ulcers (p〈0.01). Filamentous bacteria and fungi were highly specific for carcinoma (98% and p=0.02 for both comparisons). Background intestinal metaplasia was more common among gastric cancers compared with peptic ulcers (50% vs. 26%, p=0.02), whereas chemical gastropathy was more commonly associated with the latter (50% versus 10%, p〈0.01). Conclusion Gastric cancers may be colonized by non- H. pylori microbes. Detection of numerous bacterial colonies, filamentous bacteria, or fungi in biopsy material obtained from ulcerated gastric lesions should raise suspicion for underlying malignancy. This article is protected by copyright. All rights reserved.
    Print ISSN: 0309-0167
    Electronic ISSN: 1365-2559
    Topics: Medicine
    Published by Wiley-Blackwell
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  • 69
    Publication Date: 2018-03-09
    Description: Neurodegenerative diseases, the leading cause of morbidity and disability is gaining increased attention as it imposes a considerable socioeconomic impact, due in part to the ageing community. Neuronal damage is a pathological hallmark of Alzheimer's and Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, spinocerebellar ataxia and multiple sclerosis, although such damage is also observed following neurotropic viral infections, stroke, genetic white matter diseases and paraneoplastic disorders. Despite the different aetiologies e.g. infections, genetic mutations, trauma and protein aggregations, neuronal damage is frequently associated with chronic activation of an innate immune response in the CNS. The growing awareness that the immune system is inextricably involved in shaping the brain during development as well as mediating damage but also regeneration and repair, has stimulated therapeutic approaches to modulate the immune system in neurodegenerative diseases. Here, we review the current understanding of how astrocytes and microglia, as well as neurons and oligodendrocytes, shape the neuroimmune response during development, and how aberrant responses that arise due to genetic or environmental triggers may predispose the CNS to neurodegenerative diseases. We discuss the known interactions between the peripheral immune system and the brain, and review the current concepts on how immune cells enter and leave the CNS. A better understanding of neuroimmune interactions during development and disease will be key to further manipulating these responses and the development of effective therapies to improve quality of life, and reduce the impact of neuroinflammatory and degenerative diseases. This article is protected by copyright. All rights reserved.
    Print ISSN: 0019-2805
    Electronic ISSN: 1365-2567
    Topics: Medicine
    Published by Wiley-Blackwell
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  • 70
    Publication Date: 2018-03-09
    Description: High salt consumption has since long been associated with elevated blood pressure and cardiovascular disease. Recently, mouse studies suggested that a high dietary salt intake exacerbates the clinical manifestations of autoimmunity. Using naïve cells ex vivo after pre-exposure of mice to high salt intake, we show that increased salt exposure affects the viability and effector functions of immune cells. CD4 + T cells evidenced a pro-inflammatory phenotype characterized by increased secretion of IFN γ and IL-17A, when exposed to high salt concentrations in vitro . Interestingly, this phenotype was associated with osmotic pressure, since replacing salt for D-mannitol resulted in similar observations. However, high salt intake did not alter the development of T cell-dependent autoimmunity. Instead, recruitment of peritoneal macrophages was increased in mice pre-exposed to high salt concentrations. These cells had an increased production of both TNF α and IL-10, suggesting that salt stimulates expansion/differentiation of different subsets of macrophages. Moreover, mice pre-exposed to high salt intake developed exacerbated symptoms of colitis, when induced by dextran sulfate sodium. The aggravated colitis in salt exposed animals was associated with a higher frequency of CD4 + T cells and CD11b + CD64 + macrophages producing TNF α . These phenotypes correlated with elevated titers of fecal IgA and higher lymphocytic cellularity in the colon, mesenteric lymph nodes and spleen. In conclusion, we report here that high salt intake affects both lymphoid and myeloid cells ex vivo . However, the effects of high salt intake in vivo seem less pronounced in terms of CD4 + T cell responses, whereas macrophage-dependent pathologies are significantly influenced. This article is protected by copyright. All rights reserved.
    Print ISSN: 0019-2805
    Electronic ISSN: 1365-2567
    Topics: Medicine
    Published by Wiley-Blackwell
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  • 71
    Publication Date: 2018-03-09
    Description: We thank Drs. Köbel and Nelson for their deep reading and thoughtful comments on our recent review [1]. Although they raised significant concerns, their letter, in which they outline their current practice, indicates their agreement with our basic proposition that molecular, TCGA-based classification is the most important advance in endometrial cancer pathology in a very long time, and is immediately clinically actionable.
    Print ISSN: 0022-3417
    Electronic ISSN: 1096-9896
    Topics: Medicine
    Published by Wiley-Blackwell
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  • 72
    Publication Date: 2018-03-09
    Description: The development of Genetically Engineered Mouse Models (GEMMs) has catalyzed tremendous progress in cancer research. However, it has been difficult to design adequate mouse models for high-grade serous carcinoma (HGSC), the most common and lethal form of ovarian cancer. The genetic complexity of the disease, as well as the recent appreciation that most HGSCs arise from the fallopian tube (FT) secretory epithelium rather than the ovarian surface epithelium, has stifled the development of robust GEMMs. In a recent issue of this journal, Zhai et al presented an elegant mouse model for ovarian cancer that uses Ovgp1 as a FT-specific promoter to inactivate Brca1 , Trp53 , Rb1 , Nf1 and Pten . The authors showed that loss of these genes in the mouse FT epithelium can mimic the different stages of human HGSC tumorigenesis. Their robust model emphasizes the importance of considering both the cell of origin and tumor genetics in developing accurate model systems. They provide a useful tool for studying mechanisms of disease in vivo and for research into novel methods of prevention, early detection and treatment of HGSC.
    Print ISSN: 0022-3417
    Electronic ISSN: 1096-9896
    Topics: Medicine
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  • 73
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    Wiley-Blackwell
    Publication Date: 2018-03-09
    Print ISSN: 0899-1987
    Electronic ISSN: 1098-2744
    Topics: Medicine
    Published by Wiley-Blackwell
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  • 74
    Publication Date: 2018-03-09
    Description: Mass spectrometry (MS)-based immunopeptidomics has developed as one of the leading methodologies for comprehensive characterization of in vivo presented Human Leukocyte Antigen (HLA)-bound peptides. Unveiling the identity of HLA-bound peptides derived from diseased cells is crucial to gain knowledge on the constitution of efficient disease-specific T cell responses. The HLA-presented peptidome reflects the status of the cellular proteome, hence disease-related aberrations of post-translational modifications (PTMs) might lead to presentation of peptides harboring PTMs. Therefore, characterization of HLA-bound PTM peptides could shed light on their relevance in immune and disease processes. In this issue, Ramarathinam et al. investigate the presentation of HIV envelope (HIVenv) peptides bound to the HLA-B*57:01 allele. Among these peptides, the authors specifically focused on a kynurenine modified peptide. To this end, they characterize the possible origin of the kynurenine modification, its effect on HLA binding affinity, stability, conformation within the complex and its immunogenicity compared to the native counterpart. This article is protected by copyright. All rights reserved
    Print ISSN: 1615-9853
    Electronic ISSN: 1615-9861
    Topics: Medicine
    Published by Wiley-Blackwell
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  • 75
    Publication Date: 2018-03-09
    Description: Background The composition and organization of extracellular matrix (ECM) are important regulators of cell behavior. In particular in the prostate, this central role of the ECM is further stressed by the fact that several potential markers of prostate stem cells are matrix receptors. Methods We established 12 fibroblastic cell lines from cancerous and non-cancerous areas of six prostates and allowed the cells to produce ECM under cell culture conditions. We also performed a proteome wide analysis of the ECM components by mass spectrometry. To study the in vitro activation of fibroblastic cells we compared the differences between the ECM produced in cell culture by six non-cancerous-tissue-derived fibroblasts and the in vivo matrisome from the corresponding non-cancerous tissue of prostate. Results Our results suggest that at tissue level the ECM is mainly produced by fibroblastic cells and that it contains standard collagen I fibrils and fibril-associated proteins. Beaded-filament forming collagen VI is also abundant and basement membranes potentially contain five laminin subtypes and collagens XV and XVIII. As the main finding, we also detected differences when in vivo and in vitro matrisomes were compared. Only 65 out of 206 proteins were found to be common for both in vivo and in vitro samples. Majority of the 55 proteins, which were solely detected in in vivo samples, were considered to be plasma derived. Eighty-six proteins were solely found from in vitro fibroblast-derived ECM, and most of them were related to matrix remodeling or growth factor action, proposing that the activation of fibroblasts in cell culture may remarkably modify their gene expression profile. Finally, in comparison to traditional 2D in vitro cell culture, the ECM composition of 3D spheroid culture was analyzed. The matrisome in spheroid culture did not resemble the in vivo ECM more closely than in monolayer culture. Conclusions Artificial activation of ECM remodeling seems to be a distinctive feature in in vitro models. In conclusion the constitution of ECM produced by prostate derived fibroblasts in vitro is similar, but not identical to the prostate ECM in vivo as shown here by mass spectrometric analysis.
    Print ISSN: 0270-4137
    Electronic ISSN: 1097-0045
    Topics: Medicine
    Published by Wiley-Blackwell
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  • 76
    Publication Date: 2018-03-09
    Description: Increasingly researches have revealed that post-translational modifications (PTMs) occurred at lysine (PLMs) could cooperatively regulated various biological processes by crosstalk. But the trend of the crosstalk between multiply PLMs and the properties of PLM crosstalk still require explorations. In this study, the crosstalk among acetylation, succinylation, and SUMOylation were systematically deciphered in a site-specific manner. First, we detected crosstalk between SUMOylation and succinylation was under- expressed, whereas succinylation tend to crosstalk with acetylation than SUMOylation on the same lysine residue while PLMs crosstalk own a tissue-specific manner across different species. Further analyses revealed different PLMs tend to occur crosstalk at diverse subcellular compartment and structural regions, and participate in distinct biological processes and functions. In addition, short-term evolutionary analysis declared that there is no additional evolutionary pressure on PLMs crosstalk sites by comparison with singly modified sites. Finally, phylogenetic classification revealed genes with co-occupied lysine crosstalk are more likely comprising higher evolutionary similarity and possess a tendency to cluster in the specific branch. In summary, the integrated approach owns a potential for large scale prioritization of in situ crosstalk of PLMs candidates and supplies a profound understanding about the underlying relationship between different lysine modifications. This article is protected by copyright. All rights reserved
    Print ISSN: 1615-9853
    Electronic ISSN: 1615-9861
    Topics: Medicine
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