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  • Elsevier  (1,429,223)
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  • 1
    Call number: QZ269:203(3)
    Keywords: Radiation Oncology / methods ; Neoplasms / radiotherapy
    Pages: xxviii, 713 p. : ill.
    Edition: 3rd ed.
    ISBN: 9780128141281
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  • 2
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    München : Elsevier
    Call number: WN180:10(5)
    Pages: ix, 141 p. : ill.
    Edition: 5. Aufl.
    ISBN: 9783437422973
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  • 3
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    Amsterdam : Elsevier
    Call number: QZ200:575(3)/1
    Keywords: Neoplasms ; DKFZ-publications
    Notes: Contributor: Michael Baumann
    Pages: xl, 585 p. : ill.
    Edition: 3rd ed.
    ISBN: 9780128124840
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  • 4
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    Amsterdam : Elsevier
    Call number: QZ200:575(3)/2
    Keywords: Neoplasms ; DKFZ-publications
    Notes: Contributor: Michael Baumann
    Pages: xl, 577 p. : ill.
    Edition: 3rd ed.
    ISBN: 9780128124840
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  • 5
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    München : Elsevier
    Call number: QZ269:204(3)
    Keywords: Neoplasms / radiotherapy ; Radiotherapy
    Pages: xxviii, 419 p. : ill.
    Edition: 3. Aufl.
    ISBN: 9783437232923
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  • 6
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    Amsterdam : Elsevier
    Call number: QZ200:575(3)/3
    Keywords: Neoplasms ; DKFZ-publications
    Notes: Contributor: Michael Baumann
    Pages: xl, 605 p. : ill.
    Edition: 3rd ed.
    ISBN: 9780128124840
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  • 7
    Publication Date: 2018-02-02
    Description: Publication date: Available online 31 January 2018 Source: Journal of Immunological Methods Author(s): Heather L. Howie, Xiaohong Wang, Linda Kapp, Jenna Lebedev, Krystalyn E. Hudson, James C. Zimring Methods designed to monitor humoral immune responses, in a variety of settings, typically use a broadly reactive detection reagent ( e.g. polyclonal anti-Ig (immunoglobulin)) in order to characterize antibody responses. In the context of murine models of immunity, which are widely used, this would typically be antisera to mouse Ig or mouse IgG. However, there are 4 different subtypes of mouse IgG; thus, the validity of the above approach, as a general screen for humoral immune responses, depends upon the assumption that the antisera recognize all IgG subtypes. This seems like a reasonable assumption, since polyclonal antisera recognize multiple epitopes; however, herein we report that two commercial sources of goat anti-mouse Ig are hyporeactive with IgG3. Given that relative IgG3 levels are different in distinct types of immune response, these findings demonstrate a potential for misinterpretation, and suggest a need to modify immunological methods in this context.
    Print ISSN: 0022-1759
    Electronic ISSN: 1872-7905
    Topics: Medicine
    Published by Elsevier
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  • 8
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    Elsevier
    Publication Date: 2018-02-02
    Description: Publication date: Available online 31 January 2018 Source: Journal of Magnetic Resonance Author(s): Ēriks Kupče, Julien Trébosc, Barbara Perrone, Olivier Lafon, Jean-Paul Amoureux We propose a dipolar HMQC Hadamard-encoded (D-HMQC-H n ) experiment for fast 2D correlations of abundant nuclei in solids. The main limitation of the Hadamard methods resides in the length of the encoding pulses, which results from a compromise between the selectivity and the sensitivity due to losses. For this reason, these methods should mainly be used with sparse spectra, and they profit from the increased separation of the resonances at high magnetic fields. In the case of the D-HMQC-H n experiments, we give a simple rule that allows directly setting the optimum length of the selective pulses, versus the minimum separation of the resonances in the indirect dimension. The demonstration has been performed on a fully 13 C, 15 N labelled f-MLF sample, and it allowed recording the build-up curves of the 13 C- 15 N cross-peaks within 10 min. However, the method could also be used in the case of less sensitive samples, but with more accumulations. Graphical abstract
    Print ISSN: 1090-7807
    Electronic ISSN: 1096-0856
    Topics: Medicine , Physics
    Published by Elsevier
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  • 9
    Publication Date: 2018-02-02
    Description: Publication date: Available online 31 January 2018 Source: Journal of Magnetic Resonance Author(s): S. Bussandri, I. Prina, R.H. Acosta, L. Buljubasich We demonstrate that the relative phases in the refocusing pulses of multipulse sequences can compensate for pulse errors and off-resonant effects, which are commonly encountered in J -spectroscopy when CPMG is used for acquisition. The use of supercycles has been considered many times in the past, but always from the view point of time-domain NMR, that is, in an effort to lengthen the decay of the magnetization. Here we use simple spin-coupled systems, in which the quantum evolution of the system can be simulated and contrasted to experimental results. In order to explore fine details, we resort to partial J -spectroscopy, that is, to the acquisition of J -spectra of a defined multiplet, which is acquired with a suitable digital filter. We unambiguously show that when finite radiofrequency pulses are considered, the off-resonance effects on nearby multiplets affects the dynamics of the spins within the spectral window under acquisition. Moreover, the most robust phase cycling scheme for our setup consists of a 4-pulse cycle, with phases yy y ‾ y ‾ or xx x ‾ x ‾ for an excitation pulse with phase x . We show simulated and experimental results in both thermally polarized and PHIP hyperpolarized systems. Graphical abstract
    Print ISSN: 1090-7807
    Electronic ISSN: 1096-0856
    Topics: Medicine , Physics
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  • 10
    Publication Date: 2018-02-02
    Description: Publication date: Available online 31 January 2018 Source: Lung Cancer Author(s): Yutao Liu, Yan Li, Qiuxiang Ou, Xue Wu, Xiaonan Wang, Yang W. Shao, Jianming Ying Objectives Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are promising targeted therapies for EGFR -mutated non-small-cell lung cancer (NSCLC) patients. However, acquired resistance inevitably develops. Comprehensive and dynamic companion genomic diagnosis can gain insights into underlying resistance mechanisms, thereby help oncologists and patients to make informed decision on the potential benefit of the treatment. Materials and methods A 67-year-old male who was initially diagnosed of EGFR L858R-mediated NSCLC received multiple lines of chemotherapy and EGFR TKI therapies after surgery. The EGFR mutational status of individual metastatic lesion was determined by genetic testing of the tumor tissue biopsies using next generation sequencing (NGS) throughout the patient’s clinical course. An acquired potentially drug-resistant EGFR mutation was functionally validated in vitro and its sensitivity to different EGFR TKIs was assessed simultaneously. Results We have identified distinct resistance mechanisms to EGFR blockade in different metastatic lung lesions. Acquired EGFR T790M was first detected that leads to the resistance to the gefitinib treatment. Consequently, osimertinib was administrated and the response lasted until disease progressed. We identified a newly acquired EGFR L718V mutation in one lesion in conjunction with L858R, but not T790M, which showed stable disease on the following erlotinib treatment, while EGFR C797S together with L858R/T790M was detected in the other lesion that continuously progressed. In vitro functional studies demonstrated that EGFR -L858R/L718V confers resistance to osimertinib, but retains sensitivity to the second generation TKI afatinib. Conclusion We reported that distinct resistance mechanisms could arise in different metastases within the same patient in response to EGFR blockade. We also demonstrated in vitro that EGFR L718V mutation mediates resistance to osimertinib, but retains sensitivity to afatinib. We evidenced that dynamic companion genomic diagnosis offers valuable information to help define the mechanisms of drug resistance and to guide the selection of subsequent treatment.
    Print ISSN: 0169-5002
    Electronic ISSN: 1872-8332
    Topics: Medicine
    Published by Elsevier
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  • 11
    Publication Date: 2018-02-02
    Description: Publication date: Available online 1 February 2018 Source: Neuron Author(s): Naofumi Uesaka, Manabu Abe, Kohtarou Konno, Maya Yamazaki, Kazuto Sakoori, Takaki Watanabe, Tzu-Huei Kao, Takayasu Mikuni, Masahiko Watanabe, Kenji Sakimura, Masanobu Kano Elimination of redundant synapses formed early in development and strengthening of necessary connections are crucial for shaping functional neural circuits. Purkinje cells (PCs) in the neonatal cerebellum are innervated by multiple climbing fibers (CFs) with similar strengths. A single CF is strengthened whereas the other CFs are eliminated in each PC during postnatal development. The underlying mechanisms, particularly for the strengthening of single CFs, are poorly understood. Here we report that progranulin, a multi-functional growth factor implicated in the pathogenesis of frontotemporal dementia, strengthens developing CF synaptic inputs and counteracts their elimination from postnatal day 11 to 16. Progranulin derived from PCs acts retrogradely onto its putative receptor Sort1 on CFs. This effect is independent of semaphorin 3A, another retrograde signaling molecule that counteracts CF synapse elimination. We propose that progranulin-Sort1 signaling strengthens and maintains developing CF inputs, and may contribute to selection of single “winner” CFs that survive synapse elimination. Teaser Neural circuits are sculpted by eliminating redundant synapses and strengthening necessary connections depending on retrograde signals from postsynaptic neurons. Uesaka et al. demonstrate that progranulin, a multi-functional growth factor implicated in frontotemporal dementia, mediates retrograde signaling to counteract synapse elimination.
    Print ISSN: 0896-6273
    Electronic ISSN: 1097-4199
    Topics: Biology , Medicine
    Published by Elsevier on behalf of Cell Press.
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  • 12
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    Elsevier
    In: Neuron
    Publication Date: 2018-02-02
    Description: Publication date: Available online 1 February 2018 Source: Neuron Author(s): Joseph McInnes, Keimpe Wierda, An Snellinx, Laura Bounti, Yu-Chun Wang, Ilie-Cosmin Stancu, Nuno Apóstolo, Kris Gevaert, Ilse Dewachter, Tara L. Spires-Jones, Bart De Strooper, Joris De Wit, Lujia Zhou, Patrik Verstreken Synaptic dysfunction is an early pathological feature of neurodegenerative diseases associated with Tau, including Alzheimer’s disease. Interfering with early synaptic dysfunction may be therapeutically beneficial to prevent cognitive decline and disease progression, but the mechanisms underlying synaptic defects associated with Tau are unclear. In disease conditions, Tau mislocalizes into pre- and postsynaptic compartments; here we show that, under pathological conditions, Tau binds to presynaptic vesicles in Alzheimer’s disease patient brain. We define that the binding of Tau to synaptic vesicles is mediated by the transmembrane vesicle protein Synaptogyrin-3. In fly and mouse models of Tauopathy, reduction of Synaptogyrin-3 prevents the association of presynaptic Tau with vesicles, alleviates Tau-induced defects in vesicle mobility, and restores neurotransmitter release. This work therefore identifies Synaptogyrin-3 as the binding partner of Tau on synaptic vesicles, revealing a new presynapse-specific Tau interactor, which may contribute to early synaptic dysfunction in neurodegenerative diseases associated with Tau. Teaser Tau mislocalizes to presynaptic terminals in human disease conditions. Here McInnes et al. show that interaction between Tau and the presynaptic vesicle protein Synaptogyrin-3 restricts synaptic vesicle mobility, driving defects in neurotransmission in fly and mouse models of Tauopathy.
    Print ISSN: 0896-6273
    Electronic ISSN: 1097-4199
    Topics: Biology , Medicine
    Published by Elsevier on behalf of Cell Press.
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  • 13
    Publication Date: 2018-02-02
    Description: Publication date: Available online 1 February 2018 Source: Neuron Author(s): Marito Hayashi, Christopher A. Hinckley, Shawn P. Driscoll, Niall J. Moore, Ariel J. Levine, Kathryn L. Hilde, Kamal Sharma, Samuel L. Pfaff The spinal cord contains neural networks that enable regionally distinct motor outputs along the body axis. Nevertheless, it remains unclear how segment-specific motor computations are processed because the cardinal interneuron classes that control motor neurons appear uniform at each level of the spinal cord. V2a interneurons are essential to both forelimb and hindlimb movements, and here we identify two major types that emerge during development: type I neurons marked by high Chx10 form recurrent networks with neighboring spinal neurons and type II neurons that downregulate Chx10 and project to supraspinal structures. Types I and II V2a interneurons are arrayed in counter-gradients, and this network activates different patterns of motor output at cervical and lumbar levels. Single-cell RNA sequencing (RNA-seq) revealed type I and II V2a neurons are each comprised of multiple subtypes. Our findings uncover a molecular and anatomical organization of V2a interneurons reminiscent of the orderly way motor neurons are divided into columns and pools. Teaser Hayashi et al. unmask a sequential process that creates V2a interneuron subtypes arrayed in counter-gradients along the spinal cord. The unique composition of V2a networks at each spinal level drives distinct activity in motor neurons controlling the forelimb and hindlimb.
    Print ISSN: 0896-6273
    Electronic ISSN: 1097-4199
    Topics: Biology , Medicine
    Published by Elsevier on behalf of Cell Press.
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  • 14
    Publication Date: 2018-02-02
    Description: Publication date: Available online 31 January 2018 Source: Trends in Biochemical Sciences Author(s): Inês Gomes Castro, Maya Schuldiner, Einat Zalckvar The eukaryotic cell is organized as a complex grid system where membrane-bound cellular compartments, organelles, must be localized to the right place at the right time. One way to facilitate correct organelle localization and organelle cooperation is through membrane contact sites, areas of close proximity between two organelles that are bridged by protein/lipid complexes. It is now clear that all organelles physically contact each other. The main focus of this review is contact sites of peroxisomes, central metabolic hubs whose defects lead to a variety of diseases. New peroxisome contacts, their tethering complexes and functions have been recently discovered. However, if and how peroxisome contacts contribute to the development of peroxisome-related diseases is still a mystery.
    Print ISSN: 0968-0004
    Electronic ISSN: 0968-0004
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 15
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    Elsevier
    In: Neuron
    Publication Date: 2018-02-02
    Description: Publication date: Available online 1 February 2018 Source: Neuron Author(s): Nikolas A. Francis, Daniel E. Winkowski, Alireza Sheikhattar, Kevin Armengol, Behtash Babadi, Patrick O. Kanold Sensory detection tasks enhance representations of behaviorally meaningful stimuli in primary auditory cortex (A1). However, it remains unclear how A1 encodes decision-making. Neurons in A1 layer 2/3 (L2/3) show heterogeneous stimulus selectivity and complex anatomical connectivity, and receive input from prefrontal cortex. Thus, task-related modulation of activity in A1 L2/3 might differ across subpopulations. To study the neural coding of decision-making, we used two-photon imaging in A1 L2/3 of mice performing a tone-detection task. Neural responses to targets showed attentional gain and encoded behavioral choice. To characterize network representation of behavioral choice, we analyzed functional connectivity using Granger causality, pairwise noise correlations, and neural decoding. During task performance, small groups of four to five neurons became sparsely linked, locally clustered, and rostro-caudally oriented, while noise correlations both increased and decreased. Our results suggest that sensory-based decision-making involves small neural networks driven by the sum of sensory input, attentional gain, and behavioral choice. Graphical abstract Teaser Francis et al. studied the neural coding of decision-making in auditory cortex using two-photon imaging. Neural activity showed attentional gain and encoded behavioral choice. Small neuronal networks predicted behavioral choice. Functional connectivity became sparse, rostro-caudally oriented, and locally clustered during target recognition.
    Print ISSN: 0896-6273
    Electronic ISSN: 1097-4199
    Topics: Biology , Medicine
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  • 16
    Publication Date: 2018-02-03
    Description: Publication date: Available online 1 February 2018 Source: Advances in Immunology Author(s): Ronald A. Backer, Pleun Hombrink, Christina Helbig, Derk Amsen CD8 + T cells clear primary infections with intracellular pathogens and provide long-term immunity against reinfection. Two different types of CD8 + T cells are responsible for these functions: short-lived effector T cells and memory T cells. The cellular relationship between these two types of CD8 + T cells has been subject to much investigation. Both cell types can derive from a single naïve CD8 + T cell precursor. Their generation requires a fate choice early during a T cell response. As a result, two populations of T cells emerge. One of these consists of terminally differentiated short-lived effector T cells. The other contains cells able to develop into long-lived memory T cells. A foundation for development of these two populations may be laid during the first division of an activated naïve T cell precursor, as a consequence of asymmetric segregation of fate-determining factors into the daughter cells. Nonetheless, the binary choice between the two lineages is strongly influenced by signals, which ensure that the differentiation process is matched with the needs posed by the infection. Here, we will discuss the genetic and metabolic programs governing differentiation of these two lineages as well as the processes leading to their induction and consolidation to create bistability. These processes involve extensive lateral inhibition between the programs as well as positive feedback between the genetic programs and the signaling pathways responsible for their induction. These features will be highlighted by discussing the role of the Notch signaling pathway in guiding the decision between the two lineages.
    Print ISSN: 0065-2776
    Electronic ISSN: 1557-8445
    Topics: Medicine
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  • 17
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    Elsevier
    Publication Date: 2018-02-03
    Description: Publication date: Available online 1 February 2018 Source: Advances in Virus Research Author(s): Kristin Pfeffermann, Mareike Dörr, Florian Zirkel, Veronika von Messling Despite the availability of safe and effective vaccines against measles and several animal morbilliviruses, they continue to cause regular outbreaks and epidemics in susceptible populations. Morbilliviruses are highly contagious and share a similar pathogenesis in their respective hosts. This review provides an overview of morbillivirus history and the general replication cycle and recapitulates Morbillivirus pathogenesis focusing on common and unique aspects seen in different hosts. It also summarizes the state of knowledge regarding virus–host interactions on the cellular level with an emphasis on viral interference with innate immune response activation, and highlights remaining knowledge gaps.
    Print ISSN: 0065-3527
    Electronic ISSN: 1557-8399
    Topics: Medicine
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  • 18
    Publication Date: 2018-02-03
    Description: Publication date: 1 February 2018 Source: The American Journal of Human Genetics, Volume 102, Issue 2 Author(s): Anthony Drecourt, Joël Babdor, Michael Dussiot, Floriane Petit, Nicolas Goudin, Meriem Garfa-Traoré, Florence Habarou, Christine Bole-Feysot, Patrick Nitschké, Chris Ottolenghi, Metodi D. Metodiev, Valérie Serre, Isabelle Desguerre, Nathalie Boddaert, Olivier Hermine, Arnold Munnich, Agnès Rötig Neurodegeneration with brain iron accumulation (NBIA) is a genetically heterogeneous condition characterized by progressive dystonia with iron accumulation in the basal ganglia. How NBIA-associated mutations trigger iron overload remains poorly understood. After studying fibroblast cell lines from subjects carrying both known and unreported biallelic mutations in CRAT and REPS1 , we ascribe iron overload to the abnormal recycling of transferrin receptor (TfR1) and the reduction of TfR1 palmitoylation in NBIA. Moreover, we describe palmitoylation as a hitherto unreported level of post-translational TfR1 regulation. A widely used antimalarial agent, artesunate, rescued abnormal TfR1 palmitoylation in cultured fibroblasts of NBIA subjects. These observations suggest therapeutic strategies aimed at targeting impaired TfR1 recycling and palmitoylation in NBIA.
    Print ISSN: 0002-9297
    Electronic ISSN: 1537-6605
    Topics: Biology , Medicine
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  • 19
    Publication Date: 2018-02-03
    Description: Publication date: 1 February 2018 Source: The American Journal of Human Genetics, Volume 102, Issue 2 Author(s): Laura Bozal-Basterra, Itziar Martín-Ruíz, Lucia Pirone, Yinwen Liang, Jón Otti Sigurðsson, Maria Gonzalez-Santamarta, Immacolata Giordano, Estibaliz Gabicagogeascoa, Angela de Luca, Jose A. Rodríguez, Andrew O.M. Wilkie, Jürgen Kohlhase, Deborah Eastwood, Christopher Yale, Jesper V. Olsen, Michael Rauchman, Kathryn V. Anderson, James D. Sutherland, Rosa Barrio Townes-Brocks syndrome (TBS) is characterized by a spectrum of malformations in the digits, ears, and kidneys. These anomalies overlap those seen in a growing number of ciliopathies, which are genetic syndromes linked to defects in the formation or function of the primary cilia. TBS is caused by mutations in the gene encoding the transcriptional repressor SALL1 and is associated with the presence of a truncated protein that localizes to the cytoplasm. Here, we provide evidence that SALL1 mutations might cause TBS by means beyond its transcriptional capacity. By using proximity proteomics, we show that truncated SALL1 interacts with factors related to cilia function, including the negative regulators of ciliogenesis CCP110 and CEP97. This most likely contributes to more frequent cilia formation in TBS-derived fibroblasts, as well as in a CRISPR/Cas9-generated model cell line and in TBS-modeled mouse embryonic fibroblasts, than in wild-type controls. Furthermore, TBS-like cells show changes in cilia length and disassembly rates in combination with aberrant SHH signaling transduction. These findings support the hypothesis that aberrations in primary cilia and SHH signaling are contributing factors in TBS phenotypes, representing a paradigm shift in understanding TBS etiology. These results open possibilities for the treatment of TBS.
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    Electronic ISSN: 1537-6605
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  • 20
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    Elsevier
    Publication Date: 2018-02-03
    Description: Publication date: 1 February 2018 Source: The American Journal of Human Genetics, Volume 102, Issue 2 Author(s): Paul Giem
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    Electronic ISSN: 1537-6605
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  • 21
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    Elsevier
    Publication Date: 2018-02-03
    Description: Publication date: February 2018 Source: The American Journal of Medicine, Volume 131, Issue 2
    Print ISSN: 0002-9343
    Electronic ISSN: 1555-7162
    Topics: Medicine
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  • 22
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    Publication Date: 2018-02-03
    Description: Publication date: February 2018 Source: The American Journal of Medicine, Volume 131, Issue 2 Author(s): Vidya Chakravarthy, Mary J. Ryan, Amir Jaffer, Robyn Golden, Regina McClenton, Jisu Kim, Irwin Press, Tricia J. Johnson Background A primary care–staffed transition clinic is one potential strategy for reducing 30-day re-admissions for patients without an established primary care physician, but the effectiveness has not been studied. The objective was to test whether patients who completed a postdischarge transition clinic appointment were less likely to be readmitted within 30 days. Methods This retrospective cross-sectional study included adults with Medicare or Medicaid coverage who were discharged from general medicine units at Rush University Medical Center between October 2013 and October 2014. All patients had a follow-up appointment scheduled within 30 days of discharge in the transition clinic or with their primary care physician. A binary logistic regression model was constructed to test the relationship between 30-day readmission and follow-up appointment status, controlling for patient factors. Results The sample included 1149 patients with scheduled follow-up appointments (24% in the transition clinic and 76% with their primary care physician). After controlling for patient demographic characteristics and clinical factors, patients who did not complete a scheduled transition clinic appointment had approximately 3 times higher odds of readmission compared with patients who completed a transition clinic appointment (adjusted odds ratio, 2.80; P  = .004). There was no significant difference in the likelihood of 30-day readmission between patients completing a transition clinic appointment and those who were scheduled with their primary care physician. Conclusions A primary care–staffed transition clinic is a promising strategy for providing access after a recent hospitalization and effectively managing the initial posthospital discharge needs of vulnerable populations.
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    Electronic ISSN: 1555-7162
    Topics: Medicine
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  • 23
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    Publication Date: 2018-02-03
    Description: Publication date: February 2018 Source: The American Journal of Medicine, Volume 131, Issue 2 Author(s): Hiroki Matsuura
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    Electronic ISSN: 1555-7162
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  • 24
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    Publication Date: 2018-02-03
    Description: Publication date: February 2018 Source: The American Journal of Medicine, Volume 131, Issue 2 Author(s): Gregory Seymann, Robert El-Kareh, Gabrielle Schaefer, Jennifer Quartarolo
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    Electronic ISSN: 1555-7162
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  • 25
    Publication Date: 2018-02-03
    Description: Publication date: February 2018 Source: The American Journal of Medicine, Volume 131, Issue 2 Author(s): Harsh N. Patel, Jason R. Stibbe, Meghana Vellanki, Harold Paul
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  • 26
    Publication Date: 2018-02-03
    Description: Publication date: Available online 2 February 2018 Source: American Journal of Obstetrics and Gynecology Author(s): Mitchell B. Berger, Giselle E. Kolenic, Dee E. Fenner, Daniel M. Morgan, John O.L. DeLancey Background Prolapse of the anterior and posterior vaginal walls has been generally associated with apical descent and levator ani muscle defects. However, the relative contributions of these factors to the pathophysiology of descent in the different vaginal compartments is not well understood. Furthermore, symptoms uniquely associated with prolapse in these compartments have not been well-characterized. Objectives Compare associations between: 1) apical support, 2) levator ani muscles, and 3) pelvic floor symptoms in women with posterior-predominant prolapse, anterior-predominant prolapse, and normal support. Study Design This is a cross-sectional study with two case arms: 60 women with posterior prolapse, 90 with anterior prolapse, and a referent control arm with 103 asymptomatic subjects with normal support, determined from pelvic organ prolapse quantification examinations. Levator muscle defects were graded from magnetic resonance imaging. Vaginal closure forces above resting were measured with an instrumented speculum during maximal contraction. Pelvic floor symptoms were measured via the Pelvic Floor Distress Inventory – Short Form. Results Mean Point C location in controls was -6.9 cm [1.5] (mean [standard deviation]); and was higher in posterior prolapse (-4.7 cm [2.7], 2.2 cm below controls) than the anterior prolapse group (-1.2 cm [4.1]; 5.6 cm below controls, p〈0.001 for all comparisons). Normal-appearing muscles (i.e., muscle without a visible defect) occurred at similar frequencies in posterior prolapse (45%) and controls (51%, p=0.43), but less often in anterior prolapse (28%, p≤0.03 for pairwise comparisons). Major levator ani defects occurred at similar rates in women with posterior (33%) and anterior prolapse (42%, p=0.27), but less often in controls (16%, p≤0.012 for both pairwise comparisons). Similarly, there were significant differences in generated vaginal closure forces across the three groups, with the prolapse groups generating weaker closure forces than the control group (p=0.004), but the differences between the two prolapse groups were not significant after controlling for prolapse size (p=0.43). Pelvic floor symptoms were more severe for the posterior (mean Pelvic Floor Distress Inventory score 129) and anterior prolapse groups (128) than the controls (40.2, p〈0.001 for both comparisons); the difference between the two prolapse groups was not significant (p=0.83). Conclusions Posterior-predominant prolapse involves almost 3-fold less apical descent below normal than anterior-predominant vaginal prolapse. Levator ani defects and muscle impairment are also less impacted. Pelvic floor symptoms reflect the presence and size of prolapse more than the predominant lax vaginal compartment.
    Print ISSN: 0002-9378
    Electronic ISSN: 1097-6868
    Topics: Medicine
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  • 27
    Publication Date: 2018-02-03
    Description: Publication date: February 2018 Source: The American Journal of Medicine, Volume 131, Issue 2 Author(s): William S. Weintraub, Robert W. Yeh
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  • 28
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    Publication Date: 2018-02-03
    Description: Publication date: Available online 1 February 2018 Source: American Journal of Obstetrics and Gynecology Author(s): F. Bellussi, G. Pilu
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    Electronic ISSN: 1097-6868
    Topics: Medicine
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  • 29
    Publication Date: 2018-02-03
    Description: Publication date: Available online 1 February 2018 Source: American Journal of Obstetrics and Gynecology Author(s): A. Malvasi, S. Gustapane, A. Tinelli
    Print ISSN: 0002-9378
    Electronic ISSN: 1097-6868
    Topics: Medicine
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  • 30
    Publication Date: 2018-02-03
    Description: Publication date: Available online 1 February 2018 Source: Biochemical and Biophysical Research Communications Author(s): Ran Guo, Feng-Ming Zhou, Cun-Jin Su, Teng-Teng Liu, Yan Zhou, Li Fan, Zhi-Hong Wang, Xu Liu, Ya Huang, Tong Liu, Jianping Yang, Li-Hua Chen Chronic itch is a distressing symptom of many skin diseases and negatively impacts quality of life. However, there is no medication for most forms of chronic itch, although antihistamines are often used for anti-itch treatment. Epigallocatechin-3-gallate (EGCG), a major green tea polyphenol, exhibits anti-oxidative and anti-inflammatory properties. Our previous studies highlighted a key role of oxidative stress and proinflammatory cytokines in acute and chronic itch. Here, we evaluated the effects of green tea polyphenon 60 and EGCG on acute and chronic itch in mouse models and explored its potential mechanisms. The effects of EGCG were determined by behavioral tests in mouse models of acute and chronic itch, which were induced by compound 48/80, chloroquine (CQ), and 5% imiquimod cream treatment, respectively. We found that systemic or local administration of green tea polyphenon 60 or EGCG significantly alleviated compound 48/80- and chloroquine-induced acute itch in a dose-dependent manner in mice. Incubation of EGCG significantly decreased the accumulation of intracellular reactive oxygen species (ROS) directly induced by compound 48/80 and CQ in cultured ND7-23 cells, a dorsal root ganglia derived cell line. EGCG also attenuated imiquimod-induced chronic psoriatic itch behaviors and skin epidermal hyperplasia in mice. In addition, EGCG inhibited the expression of IL-23 mRNA in skin and TRPV1 mRNA in dorsal root ganglia (DRG). Finally, EGCG remarkably inhibited compound 48/80-induced phosphorylation of extracellular signal-regulated kinase (ERK) and imiquimod-induced p-AKT in the spinal cord of mice, respectively. Collectively, these results indicated EGCG could be a promising strategy for anti-itch therapy.
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  • 31
    Publication Date: 2018-02-03
    Description: Publication date: Available online 1 February 2018 Source: Biochemical and Biophysical Research Communications Author(s): Sungmin Han, Jee Youn Lee, Eun Young Heo, Il Keun Kwon, Tae Young Yune, Inchan Youn An agarose scaffold can be useful for supporting and guiding injured axons after spinal cord injury (SCI), but the electrophysiological signal of regenerated axon in scaffolds has not yet been determined. The current study investigated whether a Matrigel-loaded agarose scaffold would enhance the regeneration of axons after SCI. Moreover, the functional connectivity of regenerated axons within the channels of the scaffold was evaluated by directly recording motor evoked potentials. Our data showed that the agarose scaffold containing Matrigel can support and enhance linearly organized axon regeneration after SCI. Additionally, motor evoked potentials were successfully recorded from regenerated axons. These results demonstrate that an agarose scaffold loaded with Matrigel could promote the regeneration of axons and guide the reconnection of functional axons after SCI.
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  • 32
    Publication Date: 2018-02-03
    Description: Publication date: Available online 2 February 2018 Source: Analytical Biochemistry Author(s): Jyotsna Kailashiya Platelet-derived microparticles (PMP) are nano size fragments (100–1000 nm) released from platelets under various physiological and pathological conditions. PMP are the most abundant microparticles present in human blood. In recent past years PMP have caught attention of many clinicians as well as researchers for being associated with many diseases like cardio-vascular diseases, infections etc; and have emerged as potential biomarkers. Owing to their small size and diverse phenotype, structure and functions, microparticles including PMP render many challenges during sample handling, estimation and characterization. PMP can be analyzed for many parameters like absolute count, size distribution, functions, content, surface proteins and other phenotypic characteristics. Many techniques have been invented to analyze PMP and other extracellular vesicles for these parameters, but none of them is capable of examining all parameters alone. Apart from it, every technique has its own advantages, limitations and sets of recommendations while using it. This often leads to applying multiple techniques in combination for accurately measuring various parameters and user has to decide cautiously which technique has to be used for their selected parameter testing. This review compiles various methods, techniques, challenges during PMP analysis and recommendations based on previous studies, aimed at guiding users for selecting the most suitable techniques for their experiments with PMP.
    Print ISSN: 0003-2697
    Electronic ISSN: 1096-0309
    Topics: Biology , Chemistry and Pharmacology
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  • 33
    Publication Date: 2018-02-03
    Description: Publication date: Available online 1 February 2018 Source: Biochemical and Biophysical Research Communications Author(s): Tomoki Yamashita, Kazuo Takayama, Fuminori Sakurai, Hiroyuki Mizuguchi Human induced pluripotent stem (iPS) cell-derived hepatocyte-like cells are expected to be utilized in drug screening and regenerative medicine. However, hepatocyte-like cells have not been fully used in such applications because it is difficult to produce such cells on a large scale. In this study, we tried to establish a method to mass produce hepatocyte-like cells using a three-dimensional (3D) cell culture bioreactor called the Rotary Cell Culture System (RCCS). RCCS enabled us to obtain homogenous hepatocyte-like cells on a billion scale (>10 9  cells). The gene expression levels of some hepatocyte markers ( alpha-1 antitrypsin , cytochrome ( CYP ) 1A2 , CYP2D6 , and hepatocyte nuclear factor 4alpha ) were higher in 3D-cultured hepatocyte-like cells than in 2D-cultured hepatocyte-like cells. This result suggests that RCCS could provide more suitable conditions for hepatocyte maturation than the conventional 2D cell culture conditions. In addition, more than 90% of hepatocyte-like cells were positive for albumin and could uptake low-density lipoprotein in the culture medium. We succeeded in the large-scale production of homogenous and functional hepatocyte-like cells from human iPS cells. This technology will be useful in drug screening and regenerative medicine, which require enormous numbers of hepatocyte-like cells.
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  • 34
    Publication Date: 2018-02-03
    Description: Publication date: Available online 1 February 2018 Source: Biochemical and Biophysical Research Communications Author(s): Christian David Schmid, Kai Schledzewski, Carolin Mogler, Nina Waldburger, Viktoria Kalna, Alexander Marx, Anna Maria Randi, Cyrill Géraud, Sergij Goerdt, Philipp-Sebastian Koch Endothelial cells (EC) along the vascular tree exhibit organ-specific angiodiversity. Compared to most other ECs, liver sinusoidal endothelial cells (LSEC) that constitute the organ-specific microvasculature of the liver are morphologically and functionally unique. Previously, we showed that transcription factor Gata4 acts as a master regulator controlling LSEC differentiation. Upon analysis of the molecular signature of LSEC, we identified GPR182 as a potential LSEC-specific orphan G-protein coupled receptor (GPCR). Here, we demonstrate that GPR182 is expressed by LSEC and by EC with sinusoidal differentiation in spleen, lymph node and bone marrow in healthy human tissues. In a tissue microarray analysis of human hepatocellular carcinoma (HCC) samples, endothelial GPR182 expression was significantly reduced in tumor samples compared to peritumoral liver tissue samples (p = 0.0105). Loss of endothelial GPR182 expression was also seen in fibrotic and cirrhotic liver tissues. In vitro, GPR182 differentially regulated canonical GPCR signaling pathways as shown using reporter luciferase assays in HEK293T cells. Whereas ERK and RhoA signaling were inhibited, CREB and Calcium signaling were activated by ectopic GPR182 overexpression. Our data demonstrate that GPR182 is an endothelial subtype-specific marker for human sinusoidal EC of the liver, spleen, lymph node and bone marrow. In addition, we provide evidence for GPR182-dependent downstream signaling via ERK and SRF pathways that may be involved in regulating endothelial subtype-specific sinusoidal differentiation and sinusoidal functions such as permeability.
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  • 35
    Publication Date: 2018-02-03
    Description: Publication date: Available online 1 February 2018 Source: Biochemical and Biophysical Research Communications Author(s): Hui Li, Qiang He, Fanzhi Meng, Xu Feng, Jiang Chen, Libo Li, Jinghua Liu Methionine sulfoxide reductase B1 (MsrB1), a member of the selenoprotein family and contributes significantly to the reduction of methionine sulfoxides produced from reactive oxygen species (ROS). However, few studies have examined the role of MsrB1 in tumors. Here We tested the proliferation and invasion in MsrB1 knockdown u2os cells under H 2 O 2 /thioredoxin . As shown in our result, knockdown of MsrB1 inhibited the proliferation of u2os cells and regulates mitogen-activated protein kinase (MAPK) pathway by down-regulation of Erk, MeK phosphorylation and p53 expression in u2os cells. In a xenograft tumorigenicity mice, MsrB1 knockdown effectively inhibited tumor growth. Furthermore, MsrB1 knockdown resulted in migration and invasion reducement of u2os cells. MsrB1 regulates epithelial–mesenchymal transition (EMT) via affecting cytoskeleton by increasing E-cadherin expression and decreasing N-cadherin, TGF-β1, slug, fibronectin, vimentin, c-myc, snail and β-catenin expressions. In vivo, MsrB1 shRNAi can inhibit lung metastasis in metastasis model. In conclusion, MsrB1 regulates proliferation and invasion of u2os cells by affecting MAPK pathway and EMT, and MsrB1 gene may be a novel therapeutic target against tumors.
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  • 36
    Publication Date: 2018-02-03
    Description: Publication date: Available online 1 February 2018 Source: Biochemical and Biophysical Research Communications Author(s): Kavinash Loganathan, Shogo Moriya, Ishwar S. Parhar Gonadotrophin-releasing hormone (GnRH) expression is associated with the two-pore domain potassium ion (K + ) channel-related K + (TREK) channel trek2a expression and melatonin levels. We aimed to investigate correlation of trek2a expression with gnrh3 expression, and regulatory mechanisms of trek2a expression by the melatonin receptor Mt1 and α 2 -adrenoceptor which are regulated by melatonin. trek2a specific siRNA, Mt1 antagonist luzindole and α 2 -adrenoceptor antagonist prazosin were administered into the adult zebrafish brain and gene expressions were examined by real-time PCR. trek2a specific siRNA administration significantly reduced expression levels of trek2a , gnrh3 and mt1 . Luzindole administration suppressed trek2a and gnrh3 expressions. Prazosin administration reduced trek2a and gnrh3 expressions. It is suggested that Trek2a regulates gnrh3 expression under the control of Mt1 and α 2 -adrenoceptor.
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  • 37
    Publication Date: 2018-02-03
    Description: Publication date: Available online 1 February 2018 Source: Biochemical and Biophysical Research Communications Author(s): Veronica Venturi, Richard Little, Peter W. Bircham, Juliana Rodigheri Brito, Paul H. Atkinson, David R. Maass, Paul H. Teesdale-Spittle The translation initiation machinery is emerging as an important target for therapeutic intervention, with potential in the treatment of cancer, viral infections, and muscle wasting. Amongst the targets for pharmacological control of translation initiation is the eukaryotic initiation factor 4A (eIF4A), an RNA helicase that is essential for cap-dependent translation initiation. We set out to explore the system-wide impact of a reduction of functional eIF4A. To this end, we investigated the effect of deletion of TIF1 , one of the duplicate genes that produce eIF4A in yeast, through synthetic genetic array interactions and system-wide changes in GFP-tagged protein abundances. We show that there is a biological response to deletion of the TIF1 gene that extends through the proteostasis network. Effects of the deletion are apparent in processes as distributed as chromatin remodelling, ribosome biogenesis, amino acid metabolism, and protein trafficking. The results from this study identify protein complexes and pathways that will make ideal targets for combination therapies with eIF4A inhibitors. Graphical abstract
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  • 38
    Publication Date: 2018-02-03
    Description: Publication date: Available online 1 February 2018 Source: Biochemical and Biophysical Research Communications Author(s): Lili Wan, Matthew J. Powell-Palm, Charles Lee, Anshal Gupta, Bradley P. Weegman, Mark G. Clemens, Boris Rubinsky Isochoric (constant volume) preservation at subfreezing temperatures is being investigated as a novel method for preserving cells and organs. This study is a first initial effort to evaluate the efficacy of this method for heart preservation, and to provide a preliminary outline of appropriate preservation parameters. To establish a baseline for further studies, rat hearts were preserved in a University of Wisconsin (UW) intracellular solution for one hour under isochoric conditions at: 0 °C (atmospheric pressure - 0.1 MPa), - 4 °C (41 MPa), - 6 °C (60 MPa) and – 8 °C (78 MPa). The viability of the heart was evaluated using Langendorff perfusion and histological examination. The physiological performance of hearts preserved at – 4 °C (41 MPa) was comparable to that of a heart preserved on ice at atmospheric pressure, with no statistically significant difference in histological injury score. However, hearts preserved at −4 °C displayed substantially reduced interstitial edema compared to hearts preserved by conventional hypothermic preservation in UW on ice at atmospheric pressure, suggesting significant protection from increased vascular permeability following preservation. Hearts preserved at – 6 °C (60 MPa) suffered injury from cellular swelling and extensive edema, and at – 8 °C (78 MPa) hearts experienced significant morphological disruption. To the best of our knowledge, this is the first publication showing that a mammalian organ can survive low subfreezing temperatures without the use of a cryoprotective additive. Lowering the preservation temperature reduces metabolism and improves preservation quality, and these results suggest that improvements in preservation are possible at subzero temperatures with low to moderate pressures observed at −4 °C. Notably, tissue damage was observed at lower temperatures (−6 °C or below) accompanying further elevation of pressure associated with isochoric preservation that may prove detrimental. Therefore, subfreezing temperature isochoric preservation protocols should optimize, a combination of temperature and pressure that will minimize the negative effects of elevated pressure while retaining the beneficial effect of lower temperatures and reduced metabolism.
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  • 39
    Publication Date: 2018-02-03
    Description: Publication date: Available online 31 January 2018 Source: Biochemical and Biophysical Research Communications Author(s): Yanling Yang, Vince J. LiCata Klenow and Klentaq are the large fragment domains of the Pol I DNA polymerases from Escherichia coli and Thermus aquaticus , respectively. Herein, we show that both polymerases can significantly stimulate complementary intermolecular end-joining ligations by E.coli DNA ligase when the polymerases are present at concentrations lower than that of the DNA substrates. In contrast, high polymerase concentrations relative to the DNA substrates inhibit the intermolecular ligation activity of DNA ligase. Neither polymerase was able to stimulate the DNA ligase from T4 bacteriophage. Additionally, nick-closure by E. coli DNA ligase (but not T4 ligase) is slightly stimulated by both polymerases, but only at about 10% of the magnitude seen for end-joining enhancement. The data represent one of the first observations of direct polymerase-ligase interactions in prokaryotes, and suggest that the polymerases stabilize the associated DNA ends during intermolecular ligation, and that such a complex can be taken advantage of by some, but not all, DNA ligases.
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  • 40
    Publication Date: 2018-02-02
    Description: Publication date: Available online 31 January 2018 Source: Radiotherapy and Oncology Author(s): Philippe Bulens, Alice Couwenberg, Karin Haustermans, Annelies Debucquoy, Vincent Vandecaveye, Marielle Philippens, Mu Zhou, Olivier Gevaert, Martijn Intven Background and purpose To safely implement organ preserving treatment strategies for patients with rectal cancer, well-considered selection of patients with favourable response is needed. In this study, we develop and validate an MRI-based response predicting model. Methods A multivariate model using T2-volumetric and DWI parameters before and 6 weeks after chemoradiation (CRT) was developed using a cohort of 85 rectal cancer patients and validated in an external cohort of 55 patients that underwent preoperative CRT. Results Twenty-two patients (26%) achieved ypT0-1N0 response in the development cohort versus 13 patients (24%) in the validation cohort. Two T2-volumetric parameters (ΔVolume% and Sphere_post) and two DWI parameters (ADC_avg_post and ADCratio_avg) were retained in a model predicting (near-)complete response (ypT0-1N0). In the development cohort, this model had a good predictive performance (AUC = 0.89; 95% CI 0.80–0.98). Validation of the model in an external cohort resulted in a similar performance (AUC = 0.88 95% CI 0.79–0.98). Conclusion An MRI-based prediction model of (near-)complete pathological response following CRT in rectal cancer patients, shows a high predictive performance in an external validation cohort. The clinically relevant features in the model make it an interesting tool for implementation of organ-preserving strategies in rectal cancer.
    Print ISSN: 0167-8140
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  • 41
    Publication Date: 2018-02-02
    Description: Publication date: Available online 31 January 2018 Source: Radiotherapy and Oncology Author(s): Sarah J. Moore, Patries M. Herst, Robert J.W. Louwe Background and purpose A remarkable improvement in patient positioning was observed after the implementation of various process changes aiming to increase the consistency of patient positioning throughout the radiotherapy treatment chain. However, no tool was available to describe these changes over time in a standardised way. This study reports on the feasibility of Statistical Process Control (SPC) to highlight changes in patient positioning accuracy and facilitate correlation of these changes with the underlying process changes. Materials and methods Metrics were designed to quantify the systematic and random patient deformation as input for the SPC charts. These metrics were based on data obtained from multiple local ROI matches for 191 patients who were treated for head-and-neck cancer during the period 2011–2016. Results SPC highlighted a significant improvement in patient positioning that coincided with multiple intentional process changes. The observed improvements could be described as a combination of a reduction in outliers and a systematic improvement in the patient positioning accuracy of all patients. Conclusion SPC is able to track changes in the reproducibility of patient positioning in head-and-neck radiation oncology, and distinguish between systematic and random process changes. Identification of process changes underlying these trends requires additional statistical analysis and seems only possible when the changes do not overlap in time.
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  • 42
    Publication Date: 2018-02-02
    Description: Publication date: Available online 30 January 2018 Source: Radiotherapy and Oncology Author(s): Muhammad Shahid Iqbal, Charles Kelly, Josef Kovarik, Bojidar Goranov, Ghazia Shaikh, David Morgan, Werner Dobrowsky, Vinidh Paleri
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  • 43
    Publication Date: 2018-02-02
    Description: Publication date: Available online 30 January 2018 Source: Radiotherapy and Oncology Author(s): Dominic H. Moon, Andrew Z. Wang, Joel E. Tepper Background and purpose To evaluate the safety and efficacy of liver stereotactic body radiotherapy (SBRT), and examine potential factors impacting outcomes including prior liver-directed therapy. Materials and methods Patients with ECOG 0–1, Child-Pugh Class A or B, and primary hepatocellular carcinoma (HCC) or liver metastases unsuitable for surgical resection or ablation were eligible for a prospective single arm trial. SBRT was delivered with a CyberKnife system to 45 Gy in 3 fractions with a predetermined dose de-escalation scheme. Adverse events, local control, and survival were assessed. Results A total of 30 patients were enrolled. Eleven patients (37%) had HCC and 19 (63%) patients had liver metastases. Fourteen patients (47%) had prior liver-directed therapies including nine with liver resection, seven with trans-arterial chemoembolization, and six with radiofrequency ablation. Cumulative grade 2 and 3 acute toxicity occurred in 47% and 7% of patients, respectively. Similar rates of ≥grade 2 acute toxicity were observed between patients who had prior liver-directed treatments and those who did not. At a median follow-up of 12.7 months, 1-year local control and overall survival were 81% and 62%, respectively. Prior liver-directed therapy did not affect local control or survival. Conclusions Liver SBRT is a safe and effective treatment even in the setting of prior liver-directed surgical and ablative therapies.
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  • 44
    Publication Date: 2018-02-02
    Description: Publication date: Available online 30 January 2018 Source: Radiotherapy and Oncology Author(s): Hyun Ju Kim, Sangjoon Park, Kyoung-Jin Kim, Jinsil Seong Purpose To investigate the clinical implications of the soluble programmed cell death-ligand 1 (sPD-L1) level in hepatocellular carcinoma (HCC) patients treated with radiotherapy (RT). Materials/methods HCC patients treated with RT between June 2011 and March 2015 were prospectively recruited and sPD-L1 levels were measured using an enzyme-linked immunosorbent assay. Blood samples were obtained at the RT start, RT end, and 1-month follow-up. The associations of the sPD-L1 level with the clinical features and outcomes were analyzed. Results Fifty-three patients with HCC were included. Thirty-four patients received conventional fractionated RT with hepatic arterial infusional chemotherapy, while 19 patients received stereotactic body radiotherapy (SBRT). The initial sPD-L1 level was significantly associated with stage, tumor size, portal vein tumor thrombosis, and venous invasion. The overall-survival was significantly poorer in patients with a higher level of initial sPD-L1 (≥1.315 pg/mL). A higher level of sPD-L1 at 1 month (≥12.9 pg/mL) was significantly related to early lung metastasis. The sPD-L1 level was significantly increased after RT and the change pattern of sPD-L1 was different between two RT schemes. Conclusions The level of sPD-L1 was associated with tumor aggressiveness and outcomes, suggesting its role as a possible predictive biomarker. The increases in sPD-L1 after RT suggests that combined treatment with RT and immune checkpoint inhibitors may be a promising therapeutic strategy in HCC.
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  • 45
    Publication Date: 2018-02-03
    Description: Publication date: Available online 1 February 2018 Source: Gastroenterology Author(s): Pascal Mutz, Philippe Metz, Florian A. Lempp, Silke Bender, Bingqian Qu, Katrin Schöneweis, Stefan Seitz, Thomas Tu, Agnese Restuccia, Jamie Frankish, Christopher Dächert, Benjamin Schusser, Ronald Koschny, Georgios Polychronidis, Peter Schemmer, Katrin Hoffmann, Thomas F. Baumert, Marco Binder, Stephan Urban, Ralf Bartenschlager Background & Aims Hepatitis C virus (HCV) infection is sensitive to interferon (IFN)-based therapy whereas HBV infection is not. It is unclear whether HBV escapes detection by the IFN-mediated immune response or actively suppresses it. Moreover, little is known on how HBV and HCV influence each other in co-infected cells. We investigated interactions between HBV and the IFN-mediated immune response using HepaRG cells and primary human hepatocytes (PHHs). We analyzed the effects of HBV on HCV replication, and vice versa, at the single-cell level. Methods PHHs were isolated from liver resection tissues from HBV-, HCV- and HIV-negative patients. Differentiated HepaRG cells overexpressing the HBV receptor sodium taurocholate co-transporting polypeptide (dHepaRGNTCP) and PHHs were infected with HBV. Huh7.5 cells were transfected with circular HBV DNA genomes resembling viral covalently closed circular DNA (cccDNA), and subsequently infected with HCV; this served as a model of HBV and HCV co-infection. Cells were incubated with IFN inducers, or IFNs, and anti-viral response and viral replication were analyzed by immune fluorescence, reverse-transcription quantitative PCR, ELISAs, and flow cytometry. Results HBV infection of dHepaRGNTCP cells and PHHs neither activated nor inhibited signaling via pattern recognition receptors. Incubation of dHepaRGNTCP cells and PHHs with IFN had little effect on HBV replication or levels of cccDNA. HBV infection of these cells did not inhibit JAK–STAT signaling or upregulation of IFN-stimulated genes. In co-infected cells, HBV did not prevent IFN-induced suppression of HCV replication. Conclusions In dHepaRGNTCP cells and PHHs, HBV evades the induction of IFN and IFN-induced antiviral effects. HBV infection does not rescue HCV from the IFN-mediated response.
    Print ISSN: 0016-5085
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  • 46
    Publication Date: 2018-02-03
    Description: Publication date: Available online 1 February 2018 Source: Gastroenterology Author(s): Laurie Keefer, Olafur S. Palsson, John E. Pandolfino Chronic digestive diseases including irritable bowel syndrome, gastroesophageal reflux disease and inflammatory bowel diseases cannot be disentangled from their psychological context—the substantial burden of these diseases is co-determined by symptom and disease severity and the ability of patients to cope with their symptoms without significant interruption to daily life. The growing field of psychogastroenterology focuses on the application of scientifically-based psychological principles and techniques to the alleviation of digestive symptoms. In this clinical practice update we describe the structure and efficacy of two major classes of psychotherapy—cognitive behavior therapy and gut-directed hypnotherapy. We focus on the impact of these brain-gut psychotherapies on GI symptoms as well as their ability to facilitate improved coping, resilience and self-regulation. The importance of the gastroenterologist in the promotion of integrated psychological care cannot be understated and recommendations are provided on how to address psychological issues and make an effective referral for brain-gut psychotherapy in routine practice.
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  • 47
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    Elsevier
    Publication Date: 2018-02-03
    Description: Publication date: Available online 1 February 2018 Source: Gastroenterology Author(s): Tomoaki Matsumori, Masahiro Shiokawa, Yuzo Kodama
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  • 48
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    Elsevier
    Publication Date: 2018-02-03
    Description: Publication date: Available online 1 February 2018 Source: Gastroenterology Author(s): Philipp Jud, Alfred Triebl, Andreas Lueger
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  • 49
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    Elsevier
    Publication Date: 2018-02-03
    Description: Publication date: Available online 1 February 2018 Source: Gastroenterology Author(s): B.G.P. Koot, W.G. Leeuwenburgh - Pronk, J. Vlot
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  • 50
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    Publication Date: 2018-02-03
    Description: Publication date: Available online 1 February 2018 Source: Gastroenterology Author(s): Kyosuke Tanaka, Masaya Fujiwara, Hideki Toyoda
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  • 51
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    Publication Date: 2018-02-03
    Description: Publication date: February 2018 Source: Gynecologic Oncology, Volume 148, Issue 2
    Print ISSN: 0090-8258
    Electronic ISSN: 1095-6859
    Topics: Medicine
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  • 52
    Publication Date: 2018-02-03
    Description: Publication date: February 2018 Source: The American Journal of Medicine, Volume 131, Issue 2 Author(s): Ieva Slivovskaja, Ligita Ryliskyte, Pranas Serpytis, Rokas Navickas, Jolita Badarienė, Jelena Celutkiene, Roma Puronaite, Kristina Ryliskiene, Alma Cypiene, Egidija Rinkuniene, Vaida Sileikiene, Birute Petrauskiene, Alvydas Juocevicius, Aleksandras Laucevicius Background Metabolic syndrome, physical inactivity, and central obesity contribute to early vascular aging, which leads to increased risk of cardiovascular disease. This study aimed to assess the effect of heart rate (HR)-targeted aerobic exercise training on the indices of early vascular aging, in particular, arterial stiffness, and on anthropometric and clinical profile of metabolic syndrome subjects. Methods There were 126 metabolic syndrome subjects randomly selected. Anthropometric parameters, blood pressure (BP), blood sample, and arterial wall functional and structural parameters were obtained prior to and after the 8-week (84 patients) supervised training program. The age- and sex-matched control group (42 patients) followed the same protocol, except for the HR-targeted training program. Results In the study group, HR-targeted training was associated with decreased aortic pulse wave velocity (8.47 ± 1.40 vs 8.01 ± 1.06 m/s; P  = .005), HR ( P  〈 .001), systolic ( P  〈 .015) and diastolic ( P  〈 .004) BP, waist circumference ( P  〈 .004), total and low-density-lipid cholesterol (respectively, 6.42 ± 1.41 vs 5.89 ± 1.32, P  = .003 and 4.2 ± 1.18 vs 3.8 ± 1.21, P  = .002), and an increase in aerobic capacity ( P  〈 .001). In the control group there were no statistically significant changes of arterial stiffness parameters. Multivariate analysis revealed that reduction of arterial stiffness was BP dependent. Conclusions In subjects with metabolic syndrome, HR-targeted exercise training is associated with BP-dependent decrease in aortic stiffness and improvement of metabolic and fitness parameters.
    Print ISSN: 0002-9343
    Electronic ISSN: 1555-7162
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  • 53
    Publication Date: 2018-02-03
    Description: Publication date: February 2018 Source: The American Journal of Medicine, Volume 131, Issue 2 Author(s): Martin S. Maron, Winnie Xin, Katherine B. Sims, Rita Butler, Tammy S. Haas, Ethan J. Rowin, Robert J. Desnick, Barry J. Maron Background Fabry disease is an X-linked lysosomal storage disorder caused by the deficient activity of α-galactosidase A due to mutations in the GLA gene, which may be associated with increased left ventricular wall thickness and mimic the morphologic features of hypertrophic cardiomyopathy. Management strategies for these 2 diseases diverge, with Fabry disease–specific treatment utilizing recombinant α-galactosidase A enzyme replacement therapy. Methods We studied a prospectively assembled consecutive cohort of 585 patients (71% male) from 2 hypertrophic cardiomyopathy tertiary referral centers by screening for low α-galactosidase A activity in dried blood spots. Male patients with low α-galactosidase A activity levels and all females were tested for mutations in the GLA gene. Results In 585 patients previously diagnosed with hypertrophic cardiomyopathy, we identified 2 unrelated patients (0.34%), both with the GLA mutation encoding P.N215S , the most common mutation causing later-onset Fabry disease phenotype. These patients were both asymptomatic, a man aged 53 years and a woman aged 69 years, and demonstrated a mild cardiac phenotype with symmetric distribution of left ventricular hypertrophy. After family screening, a total of 27 new Fabry disease patients aged 2-81 years were identified in the 2 families, including 12 individuals who are now receiving enzyme replacement therapy. Conclusions These observations support consideration for routine prospective screening for Fabry disease in all patients without a definitive etiology for left ventriclar hypertrophy. This strategy would likely result, through cascade family testing, in the earlier identification of new Fabry disease–affected males and female heterozygotes who may benefit from monitoring and/or enzyme replacement therapy.
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  • 54
    Publication Date: 2018-02-03
    Description: Publication date: February 2018 Source: The American Journal of Medicine, Volume 131, Issue 2 Author(s): Subir Bhatia, Loren P. Herrera Hernandez, Amrit K. Kamboj, Katie M. Rieck
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  • 55
    Publication Date: 2018-02-03
    Description: Publication date: February 2018 Source: The American Journal of Medicine, Volume 131, Issue 2 Author(s): Ann M. Sheehy, Leslie Thompson, Bradley Flansbaum
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  • 56
    Publication Date: 2018-02-03
    Description: Publication date: February 2018 Source: The American Journal of Medicine, Volume 131, Issue 2 Author(s): Erfan Ayubi, Saeid Safiri
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  • 57
    Publication Date: 2018-02-03
    Description: Publication date: February 2018 Source: The American Journal of Medicine, Volume 131, Issue 2 Author(s): Iliana S. Hurtado Rendón, Diego Alcivar, Juan Pablo Rodriguez-Escudero, Kevin Silver Background Stress cardiomyopathy is a transient cardiac syndrome characterized by reversible left ventricular systolic dysfunction precipitated by emotional or physiologic stress. The presence of obstructive coronary artery disease has been noted in stress cardiomyopathy. Methods We describe 3 case reports of patients with acute coronary syndrome and transient wall motion abnormalities not usually seen in the distribution of coronary artery disease. Results In these 3 cases of acute myocardial infarction, the distribution of the culprit coronary occlusion was not concordant with the territory of transient wall motion abnormality. Follow-up demonstrated resolution of the wall motion abnormalities without intervention in these territories. Conclusion We believe that the physiologic stress of the acute coronary syndrome may have precipitated the stress cardiomyopathy as presented by these patients. This is the first demonstration that stress cardiomyopathy may be precipitated by acute coronary syndrome.
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  • 58
    Publication Date: 2018-02-03
    Description: Publication date: Available online 2 February 2018 Source: American Journal of Obstetrics and Gynecology Author(s): Kevin M. Hellman, Caroline S. Kuhn, Frank F. Tu, Katlyn E. Dillane, Nathan A. Shlobin, Sangeeta Senapati, Xiaojie Zhou, Wei Li, Pottumarthi V. Prasad Background The lack of non-invasive methods to study dysmenorrhea has resulted in poor understanding of the mechanisms underlying pain, insufficient diagnostic tests, and limited treatment options. To address this knowledge gap, we have developed an MRI-based strategy for continuously monitoring the uterus in relation to participants’ spontaneous pain perception. Objective The study objective was to evaluate whether MRI can detect real-time changes in myometrial activity during cramping episodes in women with dysmenorrhea, with a hand-held squeeze bulb for pain reporting. Study design Sixteen women with dysmenorrhea and ten healthy control women both on and off their menses were evaluated with MRI while not taking analgesic medication. Continuous MRI was acquired using single-shot HASTE sequence along with simultaneous reporting of pain severity with a squeeze bulb. Pearson’s coefficient was used to compare results between reviewers. Proportional differences between women with dysmenorrhea and controls on/off menses were evaluated with Fisher’s exact test. The temporal relationships between signal changes were evaluated with Monte Carlo simulations. Results Spontaneous progressive decreases in myometrial signal intensity were more frequently observed in women on their menses than in the absence of pain in the same women off their menses or participants without dysmenorrhea (p’s 〈 0.01). Women without reductions in myometrial signal intensity on their menses either had a history of endometriosis or were not in pain. Observations of myometrial events were consistently reported between two raters blinded to menstrual pain or day status (r=0.97, p〈0.001). Episodes of cramping occurred either immediately before or 32-70s after myometrial signal change onset (p’s 〈0.05). Conclusions Transient decreases in myometrial uterine T2-weighted signal intensity can be reliably measured in women with menstrual pain. The directionality of signal change and temporal relationship to pain onset suggest that cramping pain may be caused by a combination of uterine pressure and hemodynamic dysfunction.
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  • 59
    Publication Date: 2018-02-03
    Description: Publication date: Available online 2 February 2018 Source: American Journal of Obstetrics and Gynecology Author(s): Judette M. Louis, Matthew A. Koch, Uma M. Reddy, Robert M. Silver, Corette B. Parker, Francesca L. Facco, Susan Redline, Chia-Ling Nhan-Chang, Judith H. Chung, Grace W. Pien, Robert C. Basner, William A. Grobman, Deborah A. Wing, Hyagriv N. Simhan, David M. Haas, Brian M. Mercer, Samuel Parry, Daniel Mobley, Benjamin Carper, George R. Saade, Frank P. Schubert, Phyllis C. Zee Background Sleep disordered breathing (SDB) is common in pregnancy, but there are limited data on predictors. Objectives The objective of this study was to develop predictive models of SDB during pregnancy. Study Design Nulliparous women completed validated questionnaires to assess for symptoms related to snoring, fatigue, excessive daytime sleepiness insomnia and restless leg syndrome. These included questions regarding the timing of sleep and sleep duration, work schedules (e.g., shift work, night work), sleep positions, and previously diagnosed sleep disorders. Frequent snoring was defined as self-reported snoring ≥3 days per week. Participants underwent in-home portable sleep studies for SDB assessment in early (6-15 weeks’) and mid-pregnancy (22-31 weeks’). SDB was characterized using an apnea hypopnea index (AHI) that included all apneas, plus hypopneas with ≥3% oxygen desaturation. For primary analyses, an AHI ≥5 events/hour was used to define SDB. Odds ratios and 95% confidence intervals (CIs) were calculated for predictor variables. Predictive ability of the logistic models was estimated using area under the receiver-operating-characteristic curves, along with sensitivities, specificities, and positive and negative predictive values and likelihood ratios. Results Among 3705 women who were enrolled, data were available for 3,264 and 2,512 women in early and mid-pregnancy, respectively. The corresponding prevalence of SDB was 3.6% and 8.3%. At each time point in gestation, frequent snoring, chronic hypertension, greater maternal age, BMI, neck circumference, and systolic blood pressure were most strongly associated with an increased risk of SDB. Logistic regression models that included current age, BMI, and frequent snoring predicted SDB in early pregnancy, SDB in mid-pregnancy, and new onset SDB in mid-pregnancy with 10-fold cross-validated AUCs of 0.870, 0.838, and 0.809. We provide a supplement with expanded tables, integrated predictiveness and classification curves, and an Excel predicted probability calculator. Conclusion(s) Among nulliparous pregnant women, logistic regression models with just three variables (i.e., age, BMI, and frequent snoring) achieved good prediction of prevalent and incident SDB. These results can help with screening for SDB in the clinical setting and for future clinical treatment trials.
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  • 60
    Publication Date: 2018-02-03
    Description: Publication date: Available online 1 February 2018 Source: American Journal of Obstetrics and Gynecology Author(s): Alison G. Cahill, Methodius G. Tuuli, Molly J. Stout, Julia D. López, George A. Macones Background Intrapartum electronic fetal monitoring (EFM) is the most commonly used tool in obstetrics in the United States, however, which EFM patterns predict acidemia remains unclear. Objective This study was designed to describe the frequency of patterns seen in labor using modern nomenclature, and to test the hypothesis that visually interpreted patterns are associated with acidemia and morbidities in term infants. We further identified patterns prior to delivery, alone or in combination, predictive of acidemia and neonatal morbidity. Design This was a prospective cohort study of 8,580 women from 2010 to 2015. Patients were all consecutive women laboring at ≥ 37 weeks gestation with a singleton cephalic fetus. EFM patterns during the 120 minutes prior to delivery were interpreted in 10-minute epochs. Interpretation included the Category system and individual EFM patterns per the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) criteria as well as novel patterns. The primary outcome was fetal acidemia (umbilical artery pH ≤ 7.10); neonatal morbidities were also assessed. Final regression models for acidemia adjusted for nulliparity, pregestational diabetes, and advanced maternal age. Area under the receiver-operating characteristic curves (AUC) were used to assess the test characteristics of individual models for acidemia and neonatal morbidity. Results Of 8,580 women, 149 (1.7%) delivered acidemic infants. Composite neonatal morbidity was diagnosed in 757 (8.8%) neonates within the total cohort. Persistent Category I, and 10-minute period of Category III, were significantly associated with normal pH and acidemia, respectively. Total deceleration area was most discriminative of acidemia (AUC=0.76; 95% CI: 0.72-0.80), and deceleration area with any 10 minutes of tachycardia had the greatest discriminative ability for neonatal morbidity (AUC=0.77; 95% CI: 0.75-0.79). Once the threshold of deceleration area is reached the number of cesareans needed-to-be performed to potentially prevent one case of acidemia and morbidity is 5 and 6, respectively. Conclusions Deceleration area is the most predictive EFM pattern for acidemia, and combined with tachycardia for significant risk of morbidity, from the EFM patterns studied. It is important to acknowledge that this study was performed in patients delivering at or beyond 37 weeks which may limit the generalizability to preterm populations. We also did not use computerized analysis of the EFM patterns because human visual interpretation was the basis for the NICHD categories, and importantly, it is how EFM is used clinically.
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  • 61
    Publication Date: 2018-02-03
    Description: Publication date: Available online 1 February 2018 Source: American Journal of Obstetrics and Gynecology Author(s): Brandon K. Bellows, Casey R. Tak, Jessica N. Sanders, David K. Turok, Eleanor B. Schwarz Background The copper intrauterine device is the most effective form of emergency contraception and can also provide long-term contraception. The levonorgestrel intrauterine device has also been studied in combination with oral levonorgestrel for women seeking emergency contraception. However, intrauterine devices have higher upfront costs than oral methods, such as ulipristal acetate and levonorgestrel. Healthcare payers and decision makers (e.g., healthcare insurers, government programs) with financial constraints must determine if the increased effectiveness of intrauterine device emergency contraception methods are worth the additional costs. Objective To compare the cost-effectiveness of four emergency contraception strategies, ulipristal acetate, oral levonorgestrel, copper intrauterine device, and oral levonorgestrel plus same-day levonorgestrel intrauterine device, over 1 year from a United States payer perspective. Study Design Costs (2017 United States dollars) and pregnancies were estimated over 1 year using a Markov model of 1000 women seeking emergency contraception. Every 28-day cycle, the model estimated the predicted number of pregnancy outcomes (i.e., live birth, ectopic pregnancy, spontaneous abortion, or induced abortion) resulting from emergency contraception failure and subsequent contraception use. Model inputs were derived from published literature and national sources. An emergency contraception strategy was considered cost-effective if the incremental cost-effectiveness ratio (i.e., the cost to prevent one additional pregnancy) was less than the weighted average cost of pregnancy outcomes in the United States ($5167). The incremental cost-effectiveness ratios and probability of being the most cost-effective emergency contraception strategy were calculated from 1000 probabilistic model iterations. One-way sensitivity analyses were used to examine uncertainty in the cost of emergency contraception, subsequent contraception, and pregnancy outcomes as well as the model probabilities. Results In 1000 women seeking emergency contraception, the model estimated direct medical costs of $1,228,000 and 137 unintended pregnancies with ulipristal acetate, compared to $1,279,000 and 150 unintended pregnancies with oral levonorgestrel, $1,376,000 and 61 unintended pregnancies with copper intrauterine devices, and $1,558,000 and 63 unintended pregnancies with oral levonorgestrel plus same-day levonorgestrel intrauterine device. The copper intrauterine device was the most cost-effective emergency contraception strategy in the majority (63.9%) of model iterations and, compared to ulipristal acetate, cost $1957 per additional pregnancy prevented. Model estimates were most sensitive to changes in the cost of the copper intrauterine device (with higher copper intrauterine device costs, oral levonorgestrel plus same-day levonorgestrel intrauterine device became the most cost-effective option) and the cost of a live birth (with lower cost births, ulipristal acetate became the most cost-effective option). When the proportion of obese women in the population increased, the copper intrauterine device became even more most cost-effective. Conclusion Over one year, the copper intrauterine device is currently the most cost-effective emergency contraception option. Policy makers and healthcare insurance companies should consider the potential for long-term savings when women seeking emergency contraception can promptly obtain whatever contraceptive best meets their personal preferences and needs; this will require removing barriers and promoting access to intrauterine devices at emergency contraception visits.
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  • 62
    Publication Date: 2018-02-03
    Description: Publication date: Available online 1 February 2018 Source: Biochemical and Biophysical Research Communications Author(s): Yuanqi Gong, Zhihong Yu, Yi Gao, Linlin Deng, Meng Wang, Yu Chen, Jingying Li, Bin Cheng Acute lung injury (ALI) is a severe disease with high morbidity and mortality, and is characterized by devastating inflammation of the lung and increased production of reactive oxygen species (ROS). Recent studies have indicated that fatty acid binding protein (FABP4) is important in the regulation of inflammation. However, the role of FABP4 in sepsis-related ALI, and the specific mechanism of action have not been examined. In vitro , the exposure of human alveolar epithelial A549 cells to lipopolysaccharide (LPS) and recombinant FABP4 (hrFABP4) resulted in the production of pro-inflammatory cytokines, inflammatory cytokines, and ROS, while these changes were ameliorated by pretreatment with the FABP4 inhibitor BMS309403 and FABP4 siRNA. Sequentially, treatment of A549 cells with N-acetylcysteine (NAC) significantly attenuated LPS and hrFABP4-induced the generation of ROS and the release of inflammatory cytokines. In vivo , a cecal ligation and puncture (CLP)-induced ALI murine model was successfully established. Then, the mice were treated with FABP4 inhibitor BMS309403. The results showed treatment with BMS309403 improved the survival rate of CLP-induced ALI mice, and prevented lung inflammation, histopathological changes, and increase of FABP4 induced by CLP. These data indicate that FABP4 plays an important role in lung inflammation of sepsis-induced ALI. Blockade of FABP4 signaling exhibits a protective effect in a CLP-induced ALI mouse model, and in A549 cell LPS specifically induces enhanced expression of FABP4, which then causes inflammatory cytokine production by elevating the ROS level.
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    Electronic ISSN: 1090-2104
    Topics: Biology , Chemistry and Pharmacology , Physics
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  • 63
    Publication Date: 2018-02-03
    Description: Publication date: Available online 1 February 2018 Source: Biochemical and Biophysical Research Communications Author(s): Songyun Deng, Yuhang Ai, Hua Gong, Qing Feng, Xiao Li, Caixia Chen, Zhiyong Liu, Yimin Wang, Qianyi Peng, Lina Zhang Sepsis is one of the most common reasons for mortality in Intensive Care Units. As a common but severe neurological complication, sepsis associated encephalopathy (SAE) has always been ignored and there is no generally accepted treatment. In this study, we demonstrated that Mdivi-1 ameliorated brain damage assessed by Nissl staining. Furthermore, Mdivi-1 reduced TUNEL-positive cells in hippocampus, and inhibited S100 calcium binding protein B (S100B) and neuron-specific enolase (NSE) release into plasma. Biochemical analysis also showed that Mdivi-1 protected hippocampus from oxidative stresses. Western blot analysis revealed that Mdivi-1, as a Drp1 inhibitor, inhibited LPS induced dynamin-related GTPase (Drp1) increase. Interestingly, it can also attenuate LPS induced optic atrophy 1 (OPA1) and phosphorylated Drp1 (p-Drp1) decrease. Thus Mdivi-1 protected rats from SAE, and this protective effect could be associated with its inhibition of Drp1 and its activation of p-Drp1 and OPA1. Mitochondrial dynamics may be a potential pharmacological therapeutic target for treating SAE.
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  • 64
    Publication Date: 2018-02-03
    Description: Publication date: Available online 1 February 2018 Source: Biochemical and Biophysical Research Communications Author(s): Yun-Xi Zhu, Jin Yao, Chang Liu, Hai-Tao Hu, Xiu-Miao Li, Hui-Min Ge, Yun-Fan Zhou, Kun Shan, Qin Jiang, Biao Yan Excessive light exposure leads to retinal degeneration and accelerates the progression and severity of several ocular diseases, such as age-related macular degeneration (AMD) and retinitis pigmentosa. Long non-coding RNAs (LncRNAs) have emerged as important regulators of photoreceptor development and ocular diseases. In this study, we investigated the role of lncRNA-MEG3 in light-induced retinal degeneration. MEG3 expression was significantly up-regulated after light insult in vivo and in vitro. MEG3 silencing protected against light-induced retinal degeneration in vivo and light-induced photoreceptor cell apoptosis in vitro. Mechanistically, MEG3 regulated retinal photoreceptor cell function by acting as p53 decoy. MEG3 silencing decreased caspase 3/7 activity, up-regulated anti-apoptotic protein (Bcl-2) expression, and down-regulated pro-apoptotic protein (Bax) expression. Taken together, this study provides a promising method of MEG3 silencing for treating light-induced retinal degeneration.
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  • 65
    Publication Date: 2018-02-03
    Description: Publication date: Available online 1 February 2018 Source: Biochemical and Biophysical Research Communications Author(s): Wenjun Zhou, Zheng Peng, Chun Zhang, Shuangshen Liu, Yi Zhang Objective Adenomyosis is a benign gynecological disease, characterized by the malignant biological behaviors of invasion and metastasis. ILK plays an important role in intercellular adhesion and triggers the process of EMT. In this study, we investigated the role of ILK-induced EMT in the pathogenesis of adenomyosis. Methods ILK and EMT markers including E-cadherin, N-cadherin and Vimentin have been detected with Immunohistochemistry(IHC), RT-PCR and Western Blot, in normal endometrium, matched eutopic and ectopic endometrium respectively. Primary endometrial cells were isolated in order to observed the morphology features, as well as the change of invasiveness. Results Hyper-activation of ILK were detected in the adenomyosis lesions, along with the typical aberrant expression of EMT markers. Furthermore, comparing with ESCs, the EuSCs showed a more invasive and dynamic phenotype. Conclusions ILK-induced EMT is a novel mechanism in the pathogenesis of adenomyosis and may be a potential therapeutic agent for adenomyosis.
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  • 66
    Publication Date: 2018-02-03
    Description: Publication date: Available online 31 January 2018 Source: Biochemical and Biophysical Research Communications Author(s): Zhubing Li, Qiang Liu Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secretory serine protease mainly expressed in liver. Although PCSK9 has been shown to inhibit hepatitis C virus (HCV) entry and replication, whether HCV regulates PCSK9 transcription has not been well studied. PCSK9 promoter activity is modulated by numerous transcription factors including sterol-regulatory element binding protein (SREBP)-1a, -1c, −2, hepatocyte nuclear factor-1 (HNF-1), and forkhead box O3 (FoxO3). Since they are differently regulated by HCV, we studied the effects of these transcriptional factors on PCSK9 promoter activity in the context of HCV infection and replication. We demonstrated that PCSK9 promoter activity was up-regulated after HCV infection and in HCV genomic replicon cells. We also studied the effects of HCV proteins on the PCSK9 promoter activity. While HCV structural proteins core, E1, and E2 had no effect, NS2, NS3, NS3-4A, NS5A and NS5B enhanced, and p7 and NS4B decreased PCSK9 promoter activity. Furthermore, we showed that transcription factors SREBP-1c, HNF-1α and specificity protein 1 increased PCSK9 promoter activity in HCV replicon cells, whereas SREBP-1a, HNF-1β and FoxO3 had an inhibitory effect. These results demonstrated the molecular mechanisms of how HCV modulates PCSK9 promoter activity and advanced our understanding on the mutual interactions between HCV and PCSK9.
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  • 67
    Publication Date: 2018-02-03
    Description: Publication date: Available online 31 January 2018 Source: Biochemical and Biophysical Research Communications Author(s): Xing Yang, Lei Wang, Qiang Wang, Lexiang Li, Yao Fu, Junying Sun Recent studies have demonstrated that microRNA-183 (miR-183) deregulates and plays major roles in many tumors. However, the role of miR-183 in osteosarcoma (OS) pathogenesis is still largely unknown. In this study, we first over-expressed and knocked down miR-183 in MG63 and U20S cells, respectively. Functional analyses showed that ectopic expression of miR-183 suppressed MG63 cell growth, migration, and invasion in vitro and in vivo, whereas knockdown of endogenous miR-183 in U20S cells significantly enhanced these abilities. Next, we characterized low density lipoprotein receptor-related protein 6 (LRP6) as a direct target of miR-183 that interacted with the 3′-untranslated region of LRP6. Furthermore, ectopic expression of LRP6 significantly abrogated the tumor-suppressive effect induced by miR-183. Finally, miR-183 regulated the tumor-suppressive functions in MG63 cells by suppressing the LRP6-Wnt/β-catenin signaling pathway. Therefore, our study demonstrates that miR-183 is a tumor suppressor microRNA that plays a major role in OS.
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  • 68
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    Elsevier
    Publication Date: 2018-02-03
    Description: Publication date: March 2018 Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Volume 1864, Issue 3
    Print ISSN: 0925-4439
    Electronic ISSN: 1879-260X
    Topics: Biology , Chemistry and Pharmacology , Medicine , Physics
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  • 69
    Publication Date: 2018-02-03
    Description: Publication date: April 2018 Source: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, Volume 1865, Issue 4 Author(s): Nefeli Zacharopoulou, Anna Tsapara, Galatea Kallergi, Evi Schmid, Philip N. Tsichlis, Sotirios C. Kampranis, Christos Stournaras The histone demethylase KDM2B is an epigenetic factor with oncogenic properties that is regulated by the basic fibroblasts growth factor (FGF-2). It has recently been shown that KDM2B co -operates with Polycomb Group proteins to promote cell migration and angiogenesis in tumors. In the present study we addressed the role of KDM2B in regulating actin cytoskeleton signaling, cell-cell adhesion and migration of prostate tumor cells. We report here that KDM2B is functionally expressed in DU-145 prostate cancer cells, activated by FGF-2 and regulates EZH2. KDM2B knockdown induced potent up-regulation of gene transcription and protein expression of the epithelial markers E-cadherin and ZO-1, while KDM2B overexpression down-regulated the levels of both markers, suggesting control of cell adhesion by KDM2B. RhoA and RhoB protein expression and activity were diminished upon KDM2B-knockdown and upregulated in KDM2B-overexpressing cell clones. In accordance, actin reorganization with formation of stress fibers became evident in KDM2B-overexpressing cells and abolished in the presence of the Rho inhibitor C3 transferase. DU-145 cell migration was significantly enhanced in KDM2B overexpressing cells and abolished in C3-pretreated cells. Conversely, the retardation of cell migration observed in KDM2B knockdown cells was enhanced in C3-pretreated cells. These results establish a clear functional link between the epigenetic factor KDM2B and the regulation of cell adhesion and Rho-GTPases signaling that controls actin reorganization and cell migration. Graphical abstract
    Print ISSN: 0167-4889
    Electronic ISSN: 1879-2596
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  • 70
    Publication Date: 2018-02-03
    Description: Publication date: Available online 31 January 2018 Source: Biochimica et Biophysica Acta (BBA) - Reviews on Cancer Author(s): Rochelle Fletcher, Yi-Jun Wang, Robert E. Schoen, Olivera J. Finn, Jian Yu, Lin Zhang Prevention or early detection is one of the most promising strategies against colorectal cancer (CRC), the second leading cause of cancer death in the US. Recent studies indicate that antitumor immunity plays a key role in CRC prevention. Accumulating evidence suggests that immunosurveillance represents a critical barrier that emerging tumor cells have to overcome in order to sustain the course of tumor development. Virtually all of the agents with cancer preventive activity have been shown to have an immune modulating effect. A number of immunoprevention studies aimed at triggering antitumor immune response against early lesions have been performed, some of which have shown promising results. Furthermore, the recent success of immune checkpoint blockade therapy reinforces the notion that cancers including CRC can be effectively intervened via immune modulation including immune normalization, and has stimulated various immune-based combination prevention studies. This review summarizes recent advances to help better harness the immune system in CRC prevention.
    Print ISSN: 0304-419X
    Electronic ISSN: 1879-2561
    Topics: Medicine
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  • 71
    Publication Date: 2018-02-03
    Description: Publication date: Available online 31 January 2018 Source: Biochimica et Biophysica Acta (BBA) - Reviews on Cancer Author(s): Ravi Salgia, Prakash Kulkarni, Prakash S. Gill The erythropoietin-producing hepatocellular carcinoma (Eph) receptors are the largest family of receptor tyrosine kinases (RTKs) that include two major subclasses, EphA and EphB. They form an important cell communication system with critical and diverse roles in a variety of biological processes during embryonic development. However, dysregulation of the Eph/ephrin interactions is implicated in cancer contributing to tumour growth, metastasis, and angiogenesis. Here, we focus on EphB4 and review recent developments in elucidating its role in upper aerodigestive malignancies to include lung cancer, head and neck cancer, and mesothelioma. In particular, we summarize information regarding EphB4 structure/function and role in disease pathobiology. We also review the data supporting EphB4 as a potential pharmacological and immunotherapy target and finally, progress in the development of new therapeutic strategies including small molecule inhibitors of its activity is discussed. The emerging picture suggests that EphB4 is a valuable and attractive therapeutic target for upper aerodigestive malignancies.
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  • 72
    Publication Date: 2018-02-03
    Description: Publication date: 1 February 2018 Source: Cell Stem Cell, Volume 22, Issue 2 Author(s): Chia-Wei Cheng, Ömer H. Yilmaz In this issue of Cell Stem Cell , Wang et al. (2018) identify a novel link between Lpcat3-mediated phospholipid remodeling (the Lands cycle) and cholesterol biosynthesis that modulates intestinal stem cell proliferation and tumorigenesis. Notably, inhibition of cholesterol biosynthesis dampens many of the Lpcat3-deficiency-mediated effects in the intestine. Teaser In this issue of Cell Stem Cell , Wang et al. (2018) identify a novel link between Lpcat3-mediated phospholipid remodeling (the Lands cycle) and cholesterol biosynthesis that modulates intestinal stem cell proliferation and tumorigenesis. Notably, inhibition of cholesterol biosynthesis dampens many of the Lpcat3-deficiency-mediated effects in the intestine.
    Print ISSN: 1934-5909
    Electronic ISSN: 1875-9777
    Topics: Biology
    Published by Elsevier on behalf of Cell Press.
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  • 73
    Publication Date: 2018-02-03
    Description: Publication date: 1 February 2018 Source: Cell Stem Cell, Volume 22, Issue 2 Author(s): Ryo Fujita, Colin Crist Muscle stem cell regenerative capacity is rapidly lost during ex vivo culture. In this issue of Cell Stem Cell , Judson et al. (2018) show that inhibition of cytoplasmic SETD7, a lysine methyltransferase, potently expands naive, undifferentiated mouse and human muscle stem cells by restricting their progression through the myogenic program. Teaser Muscle stem cell regenerative capacity is rapidly lost during ex vivo culture. In this issue of Cell Stem Cell , Judson et al. (2018) show that inhibition of cytoplasmic SETD7, a lysine methyltransferase, potently expands naive, undifferentiated mouse and human muscle stem cells by restricting their progression through the myogenic program.
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    Topics: Biology
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  • 74
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    Elsevier
    Publication Date: 2018-02-03
    Description: Publication date: 1 February 2018 Source: Cell Stem Cell, Volume 22, Issue 2 Author(s): Douglas Sipp, Hideyuki Okano The Japanese government initiated sweeping reforms targeting regenerative medicine in 2014, accompanied by substantial investment into stem cell research and development. We survey the impact of these developments and discuss how the government is working to accelerate regenerative medicine while ensuring safety and efficacy. Teaser The Japanese government initiated sweeping reforms targeting regenerative medicine in 2014, accompanied by substantial investment into stem cell research and development. We survey the impact of these developments and discuss how the government is working to accelerate regenerative medicine while ensuring safety and efficacy.
    Print ISSN: 1934-5909
    Electronic ISSN: 1875-9777
    Topics: Biology
    Published by Elsevier on behalf of Cell Press.
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  • 75
    Publication Date: 2018-02-03
    Description: Publication date: 1 February 2018 Source: Cell Stem Cell, Volume 22, Issue 2 Author(s): Bo Wang, Xin Rong, Elisa N.D. Palladino, Jiafang Wang, Alan M. Fogelman, Martín G. Martín, Waddah A. Alrefai, David A. Ford, Peter Tontonoz Adequate availability of cellular building blocks, including lipids, is a prerequisite for cellular proliferation, but excess dietary lipids are linked to increased cancer risk. Despite these connections, specific regulatory relationships between membrane composition, intestinal stem cell (ISC) proliferation, and tumorigenesis are unclear. We reveal an unexpected link between membrane phospholipid remodeling and cholesterol biosynthesis and demonstrate that cholesterol itself acts as a mitogen for ISCs. Inhibition of the phospholipid-remodeling enzyme Lpcat3 increases membrane saturation and stimulates cholesterol biosynthesis, thereby driving ISC proliferation. Pharmacologic inhibition of cholesterol synthesis normalizes crypt hyperproliferation in Lpcat3-deficient organoids and mice. Conversely, increasing cellular cholesterol content stimulates crypt organoid growth, and providing excess dietary cholesterol or driving endogenous cholesterol synthesis through SREBP-2 expression promotes ISC proliferation in vivo . Finally, disruption of Lpcat3-dependent phospholipid and cholesterol homeostasis dramatically enhances tumor formation in Apc min mice. These findings identify a critical dietary-responsive phospholipid-cholesterol axis regulating ISC proliferation and tumorigenesis. Graphical abstract Teaser Tontonoz and colleagues show that the phospholipid remodeling enzyme Lpcat3 regulates intestinal stem cells and progenitor cells by stimulating cholesterol biosynthesis. Furthermore, enhancing cholesterol availability, either by providing it in the diet or through genetic manipulation, promotes tumorigenesis in Apc min/+ mice.
    Print ISSN: 1934-5909
    Electronic ISSN: 1875-9777
    Topics: Biology
    Published by Elsevier on behalf of Cell Press.
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  • 76
    Publication Date: 2018-02-03
    Description: Publication date: Available online 1 February 2018 Source: Current Biology Author(s): Celia Blanco, Marco Bayas, Fu Yan, Irene A. Chen A central difficulty facing study of the origin of life on Earth is evaluating the relevance of different proposed prebiotic scenarios. Perhaps the most established feature of the origin of life was the progression through an RNA World, a prebiotic stage dominated by functional RNA. We use the appearance of proteins in the RNA World to understand the prebiotic milieu and develop a criterion to evaluate proposed synthetic scenarios. Current consensus suggests that the earliest amino acids of the genetic code were anionic or small hydrophobic or polar amino acids. However, the ability to interact with the RNA World would have been a crucial feature of early proteins. To determine which amino acids would be important for the RNA World, we analyze non-biological protein-aptamer complexes in which the RNA or DNA is the result of in vitro evolution. This approach avoids confounding effects of biological context and evolutionary history. We use bioinformatic analysis and molecular dynamics simulations to characterize these complexes. We find that positively charged and aromatic amino acids are over-represented whereas small hydrophobic amino acids are under-represented. Binding enthalpy is found to be primarily electrostatic, with positively charged amino acids contributing cooperatively to binding enthalpy. Arginine dominates all modes of interaction at the interface. These results suggest that proposed prebiotic syntheses must be compatible with cationic amino acids, particularly arginine or a biophysically similar amino acid, in order to be relevant to the invention of protein by the RNA World. Graphical abstract Teaser Studying the origin of life requires evaluating proposed prebiotic scenarios. Assuming proteins arose in an RNA World, Blanco et al. analyze protein-aptamer complexes to identify crucial amino acids. Arginine dominates all interaction modes, suggesting that prebiotic syntheses must produce cationic amino acids to be on-pathway to the genetic code.
    Print ISSN: 0960-9822
    Electronic ISSN: 1879-0445
    Topics: Biology
    Published by Elsevier on behalf of Cell Press.
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  • 77
    Publication Date: 2018-02-03
    Description: Publication date: Available online 1 February 2018 Source: Current Biology Author(s): Zheng Li, Katia Bonaldi, Francisco Uribe, Jose L. Pruneda-Paz The circadian clock drives daily rhythms of many plant physiological responses, providing a competitive advantage that improves plant fitness and survival rates [ 1–5 ]. Whereas multiple environmental cues are predicted to regulate the plant clock function, most studies focused on understanding the effects of light and temperature [ 5–8 ]. Increasing evidence indicates a significant role of plant-pathogen interactions on clock regulation [ 9, 10 ], but the underlying mechanisms remain elusive. In Arabidopsis , the clock function largely relies on a transcriptional feedback loop between morning ( CCA1 and LHY )- and evening ( TOC1 )-expressed transcription factors [ 6–8 ]. Here, we focused on these core components to investigate the Arabidopsis clock regulation using a unique biotic stress approach. We found that a single-leaf Pseudomonas syringae infection systemically lengthened the period and reduced the amplitude of circadian rhythms in distal uninfected tissues. Remarkably, the low-amplitude phenotype observed upon infection was recapitulated by a transient treatment with the defense-related phytohormone salicylic acid (SA), which also triggered a significant clock phase delay. Strikingly, despite SA-modulated circadian rhythms, we revealed that the master regulator of SA signaling, NPR1 [ 11, 12 ], antagonized clock responses triggered by both SA treatment and P. syringae . In contrast, we uncovered that the NADPH oxidase RBOHD [ 13 ] largely mediated the aforementioned clock responses after either SA treatment or the bacterial infection. Altogether, we demonstrated novel and unexpected roles for SA, NPR1, and redox signaling in clock regulation by P. syringae and revealed a previously unrecognized layer of systemic clock regulation by locally perceived environmental cues. Graphical abstract Teaser Li et al. unravel Arabidopsis clock regulation by a bacterial infection. They report that a localized P. syringae infection affects clock rhythms at the whole-plant level, that systemic SA and ROS phenocopy these effects, and that NPR1 (mediates SA responses) and RBOHD (produces apoplastic ROS) antagonize and mediate these responses, respectively.
    Print ISSN: 0960-9822
    Electronic ISSN: 1879-0445
    Topics: Biology