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  • Elsevier  (1,429,222)
  • American Institute of Physics (AIP)  (154,279)
  • Sage Publications
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  • 1
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Physics Letters B 294 (1992), S. 466-478 
    ISSN: 0370-2693
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Amsterdam : Elsevier
    Physics Letters B 317 (1993), S. 474-484 
    ISSN: 0370-2693
    Source: Elsevier Journal Backfiles on ScienceDirect 1907 - 2002
    Topics: Physics
    Type of Medium: Electronic Resource
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  • 3
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    New York, NY : Elsevier
    Keywords: Biochemistry ; Enzymes
    Notes: This is a series title, single volumes see link below.
    ISSN: 1557-7988
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  • 4
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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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  • 5
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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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  • 6
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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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  • 7
    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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  • 8
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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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  • 9
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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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  • 10
    Publication Date: 2018-01-01
    Description: Publication date: 7 March 2018 Source: Journal of Theoretical Biology, Volume 440 Author(s): Adrien Fauré, Shizuo Kaji Many discrete models of biological networks rely exclusively on Boolean variables and many tools and theorems are available for analysis of strictly Boolean models. However, multilevel variables are often required to account for threshold effects, in which knowledge of the Boolean case does not generalise straightforwardly. This motivated the development of conversion methods for multilevel to Boolean models. In particular, Van Ham’s method has been shown to yield a one-to-one, neighbour and regulation preserving dynamics, making it the de facto standard approach to the problem. However, Van Ham’s method has several drawbacks: most notably, it introduces vast regions of “non-admissible” states that have no counterpart in the multilevel, original model. This raises special difficulties for the analysis of interaction between variables and circuit functionality, which is believed to be central to the understanding of dynamic properties of logical models. Here, we propose a new multilevel to Boolean conversion method, with software implementation. Contrary to Van Ham’s, our method doesn’t yield a one-to-one transposition of multilevel trajectories; however, it maps each and every Boolean state to a specific multilevel state, thus getting rid of the non-admissible regions and, at the expense of (apparently) more complicated, “parallel” trajectories. One of the prominent features of our method is that it preserves dynamics and interaction of variables in a certain manner. As a demonstration of the usability of our method, we apply it to construct a new Boolean counter-example to the well-known conjecture that a local negative circuit is necessary to generate sustained oscillations. This result illustrates the general relevance of our method for the study of multilevel logical models.
    Print ISSN: 0022-5193
    Electronic ISSN: 1095-8541
    Topics: Biology
    Published by Elsevier
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  • 11
    Publication Date: 2018-01-01
    Description: Publication date: Available online 29 December 2017 Source: Trends in Genetics
    Print ISSN: 0168-9525
    Topics: Biology
    Published by Elsevier
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  • 12
    Publication Date: 2018-01-03
    Description: Publication date: Available online 2 January 2018 Source: The American Journal of Pathology Author(s): Komal Ramani, Maria Lauda Tomasi, Joshua Berlind, Nirmala Mavila, Zhaoli Sun Alcoholic liver injury is associated with hepatic stellate cell (HSC) activation. A-kinase anchoring protein 12 (AKAP12) scaffolds protein kinase C (PKC-α) and cyclin-D1, which is regulated by its phosphorylation, and spatiotemporally controls cell proliferation, invasiveness, and chemotaxis. HSC activation induces AKAP12 expression but the role of AKAP12's scaffolding activity in liver function is unknown. Since AKAP12 phosphorylation is enhanced in ethanol-treated HSCs, we examined AKAP12's scaffolding functions in alcohol-mediated HSC activation and liver injury. AKAP12 expression, interaction, and phosphorylation was assayed in in vitro and in vivo ethanol models and human subjects by real-time PCR, co-immunoprecipitation, immunoblotting, and phospho-proteomics/phosTag. Ethanol induced AKAP12 phosphorylation in the liver and in primary HSCs, but not in hepatocytes. AKAP12's scaffolding activity for PKC-α/cyclin-D1 decreased in ethanol-treated HSCs but not hepatocytes. AKAP12 negatively regulated HSC activation, which was reversed by ethanol-mediated AKAP12 phosphorylation. AKAP12 interacted with heat shock protein 47 (HSP47) that chaperones collagen and induces its secretion. Ethanol inhibited AKAP12-HSP47 and induced HSP47–collagen interaction. Ethanol-induced phospho-AKAP12 was unable to bind to HSP47 compared to its unphosphorylated counterpart; thereby proving that ethanol-mediated phosphorylation of AKAP12 inhibited the HSP47–AKAP12 scaffold. Silencing AKAP12 facilitated the chaperoning of collagen by HSP47. Hence, AKAP12 scaffolds HSP47 and regulates collagen-HSP47 interaction. Ethanol quenches AKAP12's scaffolding activity through phosphorylation and facilitates HSC activation.
    Print ISSN: 0002-9440
    Electronic ISSN: 1525-2191
    Topics: Medicine
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  • 13
    Publication Date: 2018-01-03
    Description: Publication date: 15 January 2018 Source: Biochemical and Biophysical Research Communications, Volume 495, Issue 3 Author(s): Junsheng Wang, Bin Fu, Fuchun Lu, Xiaowu Hu, Jinshan Tang, Lixin Huang Linarin, a natural flavonoid glycoside widely found in plants, has been reported to possess anti-inflammation, neuroprotection and osteogenic properties. However, its impact on osteoclast remains unclear. In the present study, the effects of linarin on osteoclastogenesis and its underlying molecular mechanisms of action were investigated. Using the culture systems of osteoclasts derived from bone marrow macrophages (BMMs), we found that linarin dose-dependently inhibited osteoclasts formation and bone resorptive activity. The Cell Counting Kit-8 test displayed that the viability of cells was not influenced by linarin at doses up to 10 μg/mL. In addition, linarin downregulated osteoclast-related genes expression, including nuclear factor of activated T cells cytoplasmic 1 (NFATc1), tartrate resistant acid phosphatase (TRAP), osteoclast-associated receptor (OSCAR) and c-Fos, as shown by quantitative real time polymerase chain reaction (RT-qPCR). Western blot analysis further showed that linarin inhibited receptor activator of nuclear factor κB ligand (RANKL)-induced nuclear factor kappa B (NF-κB) p65 and NFATc1 activity. The present findings show that linarin exerted a potent inhibitory effect on osteoclastogenesis through RANKL-induced NF-κB signaling pathway. In conclusion, the results suggest that linarin has anti-osteoclastic effects and may serve as potential modulatory agents for the prevention and treatment of bone loss-associated diseases.
    Print ISSN: 0006-291X
    Electronic ISSN: 1090-2104
    Topics: Biology , Chemistry and Pharmacology , Physics
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  • 14
    Publication Date: 2018-01-03
    Description: Publication date: 15 January 2018 Source: Biochemical and Biophysical Research Communications, Volume 495, Issue 3 Author(s): Aklima Nasrin, Mahbub Hassan, Ping Ye How to effectively delivering therapeutic agents, including γ-secretase inhibitors (GSIs), into live cells, remains a significant challenge. This study assessed the effect of Notch signaling inhibition by examining levels of the Notch1 intracellular domain (N1ICD) in cultured oral cancer cells analyzed with random stitched images (2D) and 3D visualizations using confocal microscopy and quantitative gene analysis. Substantially, we have developed a novel method to assist the delivery of γ-secretase inhibitor, DAPT, into live cells in the presence of an effective minimum concentration of Triton-X100 (0.001%) without damaging cell activity and membrane integrity assessed with cell proliferation assays. The images obtained in this study showed that DAPT alone could not block the γ-secretase inhibitor despite inhibiting cell growth. Further analysis of quantitative gene expressions of Notch signaling canonical pathway to verify the effectiveness of the novel method for delivering inhibitor into live cells, displayed deregulation of Notch1, Delta-like ligand 1 (DLL1) and hairy and enhancer of split 1 (Hes1). Our data suggest that Notch1/Hes1 signaling pathway is deactivated using DAPT with a low dose of Triton-X100 in this cancer cells. And the finding also suggests that Notch1 could be engaged by DLL1 to promote differentiation in oral cancer cells. Using this approach, we demonstrate that Triton-X100 is a promising and effective permeabilization agent to deliver γ-secretase inhibitor DAPT into live oral epithelial cells. This strategy has the potential to implicate in the treatment of cancer diseases.
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    Electronic ISSN: 1090-2104
    Topics: Biology , Chemistry and Pharmacology , Physics
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  • 15
    Publication Date: 2018-01-03
    Description: Publication date: 15 January 2018 Source: Biochemical and Biophysical Research Communications, Volume 495, Issue 3 Author(s): C.H. Han, Z.B. Guan, P.X. Zhang, H.L. Fang, L. Li, H.M. Zhang, F.J. Zhou, Y.F. Mao, W.W. Liu Necroptosis has been found to be involved in the pathogenesis of some lung diseases, but its role in hyperoxic acute lung injury (HALI) is still unclear. This study aimed to investigate contribution of necroptosis to the pathogenesis of HALI induced by hyperbaric hyperoxia exposure in a rat model. Rats were divided into control group, HALI group, Nec-1 (necroptosis inhibitor) group and edaravone group. Rats were exposed to pure oxygen at 250 kPa for 6 h to induce HALI. At 30 min before hyperoxia exposure, rats were intraperitoneally injected with Nec-1 or edaravone, and sacrificed at 24 h after hyperoxia exposure. Lung injury was evaluated by histology, lung water to dry ratio (W/D) and bronchoalveolar lavage fluid (BALF) biochemistry; the serum and plasma oxidative stress, expression of RIP1, RIP3 and MLKL, and interaction between RIP1 and RIP3 were determined. Results showed hyperoxia exposure significantly caused damage to lung and increased necroptotic cells and the expression of RIP1, RIP3 and MLKL. Edaravone pre-treatment not only inhibited the oxidative stress in HALI, but also reduced necroptotic cells, decreased the expression of RIP1, RIP3 and MLKL and improved lung pathology. Nec-1 pretreatment inhibited necroptosis and improved lung pathology, but had little influence on oxidative stress. This study suggests hyperoxia exposure induces oxidative stress may activate necroptosis, involving in the pathology of HALI, and strategies targeting necroptosis may become promising treatments for HALI.
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  • 16
    Publication Date: 2018-01-03
    Description: Publication date: 15 January 2018 Source: Biochemical and Biophysical Research Communications, Volume 495, Issue 3 Author(s): Aiguo Yan, Tao Yue, Li Li, Wei Li, Qinghua Li, Jun Li Atherosclerotic plaque formation is characterized by the persistence of lipid-laden macrophages on the inner walls of arteries. Chronic inflammation and imbalanced macrophage function are likely to play a critical role. Herein, we investigated whether bromodomain-containing protein 7 (Brd7), a member of the bromodomain-containing protein family, regulates atherosclerosis, and if so, which mechanisms are responsible for the process. We found that Brd7 is expressed in mouse atherosclerotic plaques, and mostly in macrophages. Inhibition of Brd7 accelerates atherosclerotic lesion formation in ApoE −/− mice by promoting NF-κB–mediated inflammation. Furthermore, Brd7 inhibition alters the phenotype of macrophages and promotes plaque instability, at least partly via STAT6 signaling. Our data define a previously undescribed role of Brd7 in the development of atherosclerosis.
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  • 17
    Publication Date: 2018-01-03
    Description: Publication date: 15 January 2018 Source: Biochemical and Biophysical Research Communications, Volume 495, Issue 3 Author(s): Haitao Hu, Lanxiang Hao, Chunzhou Tang, Yunxi Zhu, Qin Jiang, Jin Yao Ultra-violet (UV) radiation causes oxidative injuries to human retinal pigment epithelium (RPE) cells. We tested the potential effect of keratinocyte growth factor (KGF) against the process. KGF receptor (KGFR) is expressed in ARPE-19 cells and primary human RPE cells. Pre-treatment with KGF inhibited UV-induced reactive oxygen species (ROS) production and RPE cell death. KGF activated nuclear-factor-E2-related factor 2 (Nrf2) signaling in RPE cells, causing Nrf2 Ser-40 phosphorylation, stabilization and nuclear translocation as well as expression of Nrf2-dependent genes ( HO1 , NOQ1 and GCLC ). Nrf2 knockdown (by targeted shRNAs) or S40T mutation almost reversed KGF-induced RPE cell protection against UV. Further studies demonstrated that KGF activated KGFR-Akt-mTORC1 signaling to mediate downstream Nrf2 activation. KGFR shRNA or Akt-mTORC1 inhibition not only blocked KGF-induced Nrf2 Ser-40 phosphorylation and activation, but also nullified KGF-mediated RPE cell protection against UV. We conclude that KGF-KGFR activates Akt-mTORC1 downstream Nrf2 signaling to protect RPE cells from UV radiation.
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  • 18
    Publication Date: 2018-01-03
    Description: Publication date: 15 January 2018 Source: Biochemical and Biophysical Research Communications, Volume 495, Issue 3 Author(s): Wonwoo Lee, Kyeong Ryang Ko, Hyun-keun Kim, Seonung Lim, Sunyoung Kim Estrogen deficiency results in an imbalance between the levels of bone-resorping osteoclasts and bone-forming osteoblasts, eventually leading to overall bone loss. Dehydrodiconiferyl alcohol (DHCA), a lignan compound originally isolated from Cucurbita moschata , has been shown to bind to estrogen receptor, and indeed exhibits various activities of estrogen, such as anti-inflammatory and anti-oxidative stress effects. In this study, we tested whether synthetic DHCA could affect the BMP-2-induced osteoblastogenesis in vitro. In MC3T3-E1 cells, DHCA promoted BMP-2-induced differentiation of osteoblasts. Consistently, the expression of three osteoblastogenic genes known to be induced by BMP-2, ALP, osteocalcin and OPG, was up-regulated by DHCA treatment. DHCA was also shown to activate the production of RUNX2 by activating Smad1/5/9 and AMPK. Data from transient transfection assays suggested that DHCA might activate the estrogen receptor signaling pathway. Effects of DHCA on BMP-2-induced osteoblastogenesis were reduced when cells were treated with a specific siRNA to ERα or ERβ. Taken together, our results suggest that DHCA may be developed as an efficient therapeutic for osteoporosis by regulating osteoblastogenesis through its estrogenic effects.
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  • 19
    Publication Date: 2018-01-03
    Description: Publication date: 15 January 2018 Source: Biochemical and Biophysical Research Communications, Volume 495, Issue 3 Author(s): Sabbir Khan, Anjaneyulu Kowluru The cluster of differentiation 36 (CD36) is implicated in the intake of long-chain fatty acids and fat storage in various cell types including the pancreatic beta cell, thus contributing to the pathogenesis of metabolic stress and diabetes. Recent evidence indicates that CD36 undergoes post-translational modifications such as acetylation-deacetylation. However, putative roles of such modifications in its functional activation and onset of beta cell dysregulation under the duress of glucolipotoxicity (GLT) remain largely unknown. Using pharmacological approaches, we validated, herein, the hypothesis that acetylation-deacetylation signaling steps are involved in CD36-mediated lipid accumulation and downstream apoptotic signaling in pancreatic beta (INS-1832/13) cells under GLT. Exposure of these cells to GLT resulted in significant lipid accumulation without affecting the CD36 expression. Sulfo- n -succinimidyl oleate (SSO), an irreversible inhibitor of CD36, significantly attenuated lipid accumulation under GLT conditions, thus implicating CD36 in this metabolic step. Furthermore, trichostatin A (TSA) or valproic acid (VPA), known inhibitors of lysine deacetylases, markedly suppressed GLT-associated lipid accumulation with no discernible effects on CD36 expression. Lastly, SSO or TSA prevented caspase 3 activation in INS-1832/13 cells exposed to GLT conditions. Based on these findings, we conclude that an acetylation-deacetylation signaling step might regulate CD36 functional activity and subsequent lipid accumulation and caspase 3 activation in pancreatic beta cells exposed to GLT conditions. Identification of specific lysine deacetylases that control CD36 function should provide novel clues for the prevention of beta-cell dysfunction under GLT.
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  • 20
    Publication Date: 2018-01-03
    Description: Publication date: 15 January 2018 Source: Biochemical and Biophysical Research Communications, Volume 495, Issue 3 Author(s): Ayako Miyazawa, Satoru Ito, Shuichi Asano, Ichidai Tanaka, Mitsuo Sato, Masashi Kondo, Yoshinori Hasegawa Expression of programmed death-ligand 1 (PD-L1) in tumor cells such as lung cancer cells plays an important role in mechanisms underlying evasion of an immune check point system. Lung cancer tissue with increased deposition of extracellular matrix is much stiffer than normal lung tissue. There is emerging evidence that the matrix stiffness of cancer tissue affects the phenotypes and properties of cancer cells. Nevertheless, the effects of substrate rigidity on expression of PD-L1 in lung cancer cells remain elusive. We evaluated the effects of substrate stiffness on PD-L1 expression in HCC827 lung adenocarcinoma cells by using polyacrylamide hydrogels with stiffnesses of 2 and 25 kPa. Expression of PD-L1 protein was higher on the stiffer substrates (25 kPa gel and plastic dish) than on the soft 2 kPa gel. PD-L1 expression was reduced by detachment of cells adhering to the substrate. Interferon-γ enhanced expression of PD-L1 protein cultured on stiff (25 kPa gel and plastic dishes) and soft (2 kPa gel) substrates and in the cell adhesion-free condition. As the stiffness of substrates increased, formation of actin stress fiber and cell growth were enhanced. Transfection of the cells with short interfering RNA for PD-L1 inhibited cell growth without affecting stress fiber formation. Treatment of the cells with cytochalasin D, an inhibitor of actin polymerization, significantly reduced PD-L1 protein levels. Taken together, a stiff substrate enhanced PD-L1 expression via actin-dependent mechanisms in lung cancer cells. It is suggested that stiffness as a tumor environment regulates PD-L1 expression, which leads to evasion of the immune system and tumor growth.
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  • 21
    Publication Date: 2018-01-03
    Description: Publication date: 15 January 2018 Source: Biochemical and Biophysical Research Communications, Volume 495, Issue 3 Author(s): Yu-Ze Song, Ji-Feng Li Circular RNAs (circRNAs) is a novel type of non-coding RNAs generated from back splicing, which has been verified to mediate multiple tumorigenesis. However, the role of circRNA in osteosarcoma is still unclear. In the present study, we preliminarily screened the circRNAs expression profiles in osteosarcoma and investigated the potential regulation mechanism. The circRNAs expression profiles in osteosarcoma were screened using circRNA microarray analysis, and results showed that there were 1152 circRNAs up-regulated and 915 circRNAs down-regulated in tumor tissue compared to adjacent tissue. Hsa_circ_0001564, located at 5q35.3 and its associated-gene symbol is CANX, was one of the significantly overexpressed circRNAs in osteosarcoma tissue, as well as in osteosarcoma cell lines. In functional experiments, hsa_circ_001564 knockdown significantly suppressed the proliferation activity, induced cell cycle arrest in G0/G1 phase, and promoted apoptosis in HOS and MG-63 cells. Subsequently, we explored the probable mechanism of hsa_circ_001564, and fortunately, bioinformatics analysis revealed that miR-29c-3p contained the complementary binding region with hsa_circ_0001564, which was confirmed by dual-luciferase reporter assay. Moreover, rescue experiments illustrated that miR-29c-3p could reverse the oncogenesis effect of hsa_circ_001564. Our study discovers that hsa_circ_0001564 acts as miR-29c-3p sponge to mediate the tumorigenicity, which could act as a potential biomarker for the osteosarcoma and provide a novel insight for competing endogenous RNAs (ceRNAs) mechanism in osteosarcoma.
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  • 22
    Publication Date: 2018-01-03
    Description: Publication date: 15 January 2018 Source: Biochemical and Biophysical Research Communications, Volume 495, Issue 3 Author(s): Tiffany DeVine, Rosalie C. Sears, Mu-Shui Dai Histone H2B monoubiquitination plays a critical role in the regulation of gene transcription. Deregulation of H2B monoubiquitination contributes to human pathologies, such as cancer. Here we report that human USP36 is a novel H2Bub1 deubiquitinase. We show that USP36 interacts with H2B and deubiquitinates H2Bub1 in cells and in vitro . Overexpression of USP36 markedly reduced the levels of H2Bub1 in cells. Using the p21 gene as a model, we demonstrate that depletion of USP36 increases H2Bub1 at the p21 locus, primarily within its gene body. Consistently, knockdown of USP36 induced the expression of p21 and inhibits cell proliferation. Together, our results reveal USP36 as a novel H2B deubiquitinase and shed light on its additional functions in regulating gene expression.
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  • 23
    Publication Date: 2018-01-03
    Description: Publication date: 15 January 2018 Source: Biochemical and Biophysical Research Communications, Volume 495, Issue 3 Author(s): Kazuya Miyashita, Kenji Kitajima, Susumu Goyama, Toshio Kitamura, Takahiko Hara T cell acute lymphoblastic leukemia (T-ALL) is a malignant cancer with poor prognosis. The transcriptional co-factor LIM domain only 2 (LMO2) and its target gene HHEX are essential for self-renewal of T cell precursors and T-ALL etiology. LMO2 directly associates with LDB1 in a large DNA-containing nuclear complex and controls the transcription of T-ALL-related genes. Recently, we reported that overexpression of the LIM-homeodomain transcription factor, Lhx2, results in liberation of the Lmo2 protein from the Lmo2-Ldb1 complex, followed by ubiquitin proteasome mediated degradation. Here, we found that proliferation of five human T-ALL-derived cell lines, including CCRF-CEM, was significantly suppressed by retroviral overexpression of Lhx2. The majority of Lhx2-transduced CCRF-CEM cells arrested in G 0 phase and subsequently underwent apoptosis. Expression of LMO2 protein as well as HHEX , ERG , HES1 and MYC genes was repressed in CCRF-CEM cells by transduction with Lhx2. Lhx2-mediated growth inhibition was partially rescued by simultaneous overexpression of Lmo2; however, both the C-terminal LIM domain and the homeodomain of Lhx2 were required for its growth-suppressive activity. These data indicate that Lhx2 is capable of blocking proliferation of T-ALL-derived cells by both LMO2-dependent and -independent means. We propose Lhx2 as a new molecular tool for anti-T-ALL drug development.
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  • 24
    Publication Date: 2018-01-03
    Description: Publication date: Available online 2 January 2018 Source: Leukemia Research Author(s): Stephen A. Strickland, Aaron C. Shaver, Michael Byrne, Robert D. Daber, P. Brent Ferrell, David R. Head, Sanjay R. Mohan, Claudio A. Mosse, Tamara K. Moyo, Thomas P. Stricker, Cindy Vnencak-Jones, Michael R. Savona, Adam C. Seegmiller The National Comprehensive Cancer Network (NCCN) defines the following types of acute myeloid leukemia (AML) as favorable-risk: acute promyelocytic leukemia with t(15;17) (APL); AML with core-binding factor (CBF) rearrangements, including t(8;21) and inv(16) or t(16;16) without mutations in KIT (CBF- KIT wt ); and AML with normal cytogenetics and mutations in NPM1 ( NPM1 mut ); or biallelic mutations in CEBPA ( CEBPA mut/mut ), without FLT3-ITD. Although these AMLs are categorized as favorable risk by NCCN, clinical experience suggests that there are differences in clinical outcome amongst these cytogenetically and molecularly distinct leukemias. This study compared clinical and genotypic characteristics of 60 patients with favorable-risk AML, excluding APL, and demonstrated significant differences between them. Patients with NPM1 mut AML were significantly older than those in the other groups. Targeted next-generation sequencing on DNA from peripheral blood or bone marrow revealed significantly more mutations in NPM1 mut AML than the other favorable-risk diseases, especially in genes related to DNA splicing and methylation. CEBPA mut/mut AMLs exhibited more mutations in transcription-related genes. Patients with NPM1 mut AML and CEBPA mut/mut AML show significantly reduced overall survival in comparison with CBF- KIT wt AML. These findings emphasize that favorable-risk AML patients have divergent outcomes and that differences in clinical and genotypic characteristics should be considered in their evaluation and management.
    Print ISSN: 0145-2126
    Electronic ISSN: 1873-5835
    Topics: Medicine
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  • 25
    Publication Date: 2018-01-03
    Description: Publication date: Available online 2 January 2018 Source: Leukemia Research Author(s): Ambrus Gángó, Réka Mózes, Zsófia Boha, Béla Kajtár, Botond Timár, Péter Attila Király, Richárd Kiss, Viktória Fésüs, Noémi Nagy, Judit Demeter, Gábor Körösmezey, Zita Borbényi, Imelda Marton, Anita Szőke, Tamás Masszi, Péter Farkas, Judit Várkonyi, Márk Plander, Éva Pósfai, Miklós Egyed, Katalin Pál, Gáspár Radványi, Aryan Hamed, Judit Csomor, András Matolcsy, Donát Alpár, Csaba Bödör Background Philadelphia negative myeloproliferative neoplasms (MPNs) are characterized by frequent mutations of driver genes including JAK2 , CALR and MPL . While the influence of JAK2 V617F mutant allele burden on the clinical phenotype of MPN patients is well-described, the impact of CALR mutant allele burden on clinical features needs further investigation. Patients and methods Quantitative assessment of JAK2 and CALR mutations was performed on diagnostic DNA samples from 425 essential thrombocythemia (ET) and 227 primary myelofibrosis patients using real-time quantitative PCR and fragment length analysis. Characterization of CALR mutations and detection of MPL mutations were performed by Sanger sequencing. Results Twelve novel CALR mutations have been identified. ET patients with CALR mut load exceeding the median value exhibited lower haemoglobin values (12.0 vs. 13.6 g/dL), higher LDH levels (510 vs. 351 IU/L) and higher rate of myelofibrotic transformation (19% vs. 5%). The CALR mut load was higher among ET patients presenting with splenomegaly compared to those without splenomegaly (50.0% vs. 43.5%). Conclusion Our study confirms the clinical significance of driver mutational status and JAK2 mut load in MPNs; in addition, unravels a novel clinical association between high CALR mut load and a more proliferative phenotype in ET.
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  • 26
    Publication Date: 2018-01-03
    Description: Publication date: Available online 2 January 2018 Source: Urology Author(s): Felix Y. Yap, Darryl H. Hwang, Steven Y. Cen, Bino A. Varghese, Bhushan Desai, Brian D. Quinn, Megha Nayyar Gupta, Nieroshan Rajarubendra, Mihir M. Desai, Manju Aron, Gangning Liang, Monish Aron, Inderbir S. Gill, Vinay A. Duddalwar Objectives To investigate whether morphologic analysis can differentiate benign versus malignant renal tumors on clinically acquired imaging. Methods Between 2009 and 2014, 3D tumor volumes were manually segmented from contrast-enhanced computerized tomography (CT) images from 150 patients with predominantly solid, non-macroscopic fat-containing renal tumors: 100 renal cell carcinomas (RCC) and 50 benign lesions (e.g. oncocytoma, lipid-poor angiomyolipoma). Tessellated 3D tumor models were created from segmented voxels using MATLAB code. Eleven shape descriptors were calculated: sphericity, compactness, mean radial distance (RD), RD standard deviation, RD area ratio, zero crossings, entropy, Feret ratio, convex hull area (CHA) and perimeter (CHP) ratios, and elliptic compactness (EC). Morphometric parameters were compared using Wilcoxon rank-sum test to investigate whether malignant renal masses demonstrate more morphologic irregularity than benign ones. Results Only CHP in sagittal orientation (median 0.96 vs. 0.97) and EC in coronal orientation (median 0.92 vs. 0.93) differed significantly between malignant and benign masses (p = 0.04). When comparing these two metrics between coronal and sagittal orientations, similar but nonsignificant trends emerged (p = 0.07). Other metrics tested were not significantly different in any imaging plane. Conclusions Computerized image analysis is feasible using shape descriptors that otherwise cannot be visually assessed and used without quantification. Shape analysis via the transverse orientation may be reasonable, but encompassing all three planar dimensions to characterize tumor contour can achieve a more comprehensive evaluation. Two shape metrics (CHP and EC) may help distinguish benign from malignant renal tumors, an often challenging goal to achieve on imaging and biopsy.
    Print ISSN: 0090-4295
    Electronic ISSN: 1527-9995
    Topics: Medicine
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  • 27
    Publication Date: 2018-01-03
    Description: Publication date: Available online 2 January 2018 Source: Urology Author(s): Nima Almassi, Michelle Ponziano, Howard B. Goldman, Eric A. Klein, Andrew J. Stephenson, Venkatesh Krishnamurthi Objective – To evaluate the frequency with which preoperative medical evaluations lead to changes in perioperative management of patients undergoing radical cystectomy and to examine the impact of an evidence-based algorithm on referral utilization. Methods – A retrospective review of 176 patients undergoing radical cystectomy in 2013-2014 was conducted. Patients referred for additional preoperative medical or cardiology evaluation were identified and the incidence of diagnostic testing or management changes resulting from such evaluations determined. The impact of an evidence-based algorithm on referral utilization and identification of patients undergoing changes in perioperative management was examined. Results – 111 of 176 patients underwent additional preoperative medical evaluation, with 2.7% undergoing additional diagnostic testing and 8.1% experiencing resultant changes in medical management. Perioperative management changes were minor in scope, with the majority (65%) involving management of hypertension or hypokalemia. Perioperative outcomes were similar between patients undergoing urologic evaluation alone and patients referred for additional preoperative medical evaluation. Applying a referral algorithm incorporating American College of Cardiology guidelines would have avoided 72% of all medical referrals and reduced direct hospital costs of preoperative evaluations by 74%, while still capturing 94% of all patients who underwent perioperative management changes and all patients with diagnostic findings necessitating surgical delay. Conclusions – Preoperative medical evaluation of patients undergoing radical cystectomy infrequently yields perioperative management changes. The algorithm presented would significantly reduce overutilization and direct hospital costs while capturing patients most likely to benefit from additional medical evaluation.
    Print ISSN: 0090-4295
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  • 28
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    Elsevier
    In: Urology
    Publication Date: 2018-01-03
    Description: Publication date: Available online 2 January 2018 Source: Urology Author(s): Néha Sihra, Mohamed Aboelsoud, Abisola Oliyide, Andrew Counsell, Zara Gall
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  • 29
    Publication Date: 2018-01-04
    Description: Publication date: Available online 3 January 2018 Source: American Journal of Obstetrics and Gynecology Author(s): Stephanie Roberge, Emmanuel Bujold, Kypros H. Nicolaides Background Impaired placentation in the first 16 weeks of pregnancy is associated with increased risk of subsequent development of preeclampsia, birth of small for gestational age neonates and placental abruption. Previous studies reported that prophylactic use of aspirin reduces the risk of preeclampsia and small for gestational age neonates with no significant effect on placental abruption. However, meta-analyses of randomized controlled trials examining the effect of aspirin in relation to gestational age at onset of therapy and dose of the drug reported that significant reduction in the risk of preeclampsia and small for gestational age neonates is achieved only if the onset of treatment is at ≤16 weeks of gestation and the daily dose of the drug is ≥100 mg. Objective To estimate the effect of aspirin on the risk of placental abruption or antepartum hemorrhage, in relation to gestational age at onset of therapy and the dose of the drug. Study design We performed a systematic review and meta-analysis of randomized controlled trials that evaluated the prophylactic effect of aspirin during pregnancy using PubMed, Cinhal, Embase, Web of Science and Cochrane library from 1985 to September 2017. Relative risks (RR) of placental abruption or antepartum hemorrhage with their 95% confidence intervals (95% CI) were calculated using random effect models. Analyses were stratified according to daily dose of aspirin (〈100 and ≥100 mg) and the gestational age at the onset of therapy (≤16 and >16 weeks) and compared using subgroup difference analysis. Results The entry criteria were fulfilled by 20 studies on a combined total of 12,585 participants. Aspirin at a dose of 〈100 mg per day had no impact on the risk of placental abruption or antepartum hemorrhage, irrespective of whether it was initiated at ≤16 weeks’ gestation (RR 1.11, 95% CI 0.52 to 2.36) or at >16 weeks (RR 1.32, 95% CI 0.73 to 2.39). At ≥100 mg per day, aspirin was not associated with a significant change on the risk of placental abruption or antepartum hemorrhage, whether the treatment was initiated at ≤16 weeks of gestation (RR 0.62, 95% CI 0.31 to 1.26), or at >16 weeks (RR 2.08 95% CI 0.86 to 5.06), but the difference between the subgroups was significant (p=0.04). Conclusion Aspirin at a daily dose of ≥100 mg for prevention of preeclampsia, initiated at ≤16 weeks of gestation rather than >16 weeks may decrease the risk of placental abruption or antepartum hemorrhage.
    Print ISSN: 0002-9378
    Electronic ISSN: 1097-6868
    Topics: Medicine
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  • 30
    Publication Date: 2018-01-04
    Description: Publication date: January 2018 Source: American Journal of Obstetrics and Gynecology, Volume 218, Issue 1, Supplement Author(s): Sara Ornaghi, Jun-Ping Bai, Dhasakumar Navaratnam, Joseph Santos-Sacchi, Patrizia Vergani, Anthony van den Pol, Michael J. Paidas
    Print ISSN: 0002-9378
    Electronic ISSN: 1097-6868
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  • 31
    Publication Date: 2018-01-04
    Description: Publication date: Available online 3 January 2018 Source: Blood Cells, Molecules, and Diseases Author(s): Maria Rosa Lidonnici, Giuliana Ferrari Gene therapy for hemoglobinopathies is currently based on transplantation of autologous hematopoietic stem cells genetically modified with an integrating lentiviral vector expressing a globin gene under the control of globin transcriptional regulatory elements. Studies and safety works demonstrated the potential therapeutic efficacy and safety of this approach, providing the rationale for clinical translation. The outcomes of early clinical trials, although showing promising results, have highlighted the current limitations to a more general application. These include the nature, source and age of repopulating hematopoietic stem cells, the suboptimal transduction efficiency and gene expression levels, the toxicity and efficacy of bone marrow conditioning, the stress status of bone marrow microenvironment in chronic diseases such as β-thalassemia and sickle cell disease. Recently, gene editing strategies based on the use of nucleases offered a novel approach to increase globin expression in a quasi-physiological way, independently from the addition of transgenes and viral sequences to the human genome. This review will discuss the current status of gene therapy for β-thalassemia and sickle cell disease with a perspective towards the improvements necessary in the context of clinical translation.
    Print ISSN: 1079-9796
    Electronic ISSN: 1096-0961
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  • 32
    Publication Date: 2018-01-04
    Description: Publication date: Available online 3 January 2018 Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease Author(s): Yingying Yang, Panpan Dong, Jing Zhao, Wei Zhou, Yonghua Zhou, Yongliang Xu, Congjin Mei, Fukun Guo, Yi Zheng, Jun-Qi Yang Asthma is a chronic airway inflammation in which Th2 and Th17 cells play critical roles in its pathogenesis. We have reported that atypical protein kinase (PKC) λ/ι is a new regulator for Th2 differentiation and function. However, the role of PKCλ/ι for Th17 cells remains elusive. In this study, we explored the effect of PKCλ/ι on Th17 cells in the context of ex vivo cell culture systems and an in vivo murine model of allergic airway inflammation with the use of activated T cell-specific conditional PKCλ/ι-deficient mice. Our findings indicate that PKCλ/ι regulates Th17 cells. The secretion of Th17 effector cytokines, including IL-17, IL-21 and IL-22, were inhibited from PKCλ/ι-deficient T cells under non-skewing or Th17-skewing culture conditions. Moreover, the impaired Th17 differentiation and function by the PKCλ/ι-deficiency was associated with the downregulation of Stat3 and Rorγt, key Th17 transcription factors. We developed a model of Th17 and neutrophil-involved allergic airway inflammation by intratracheal inoculation of house dust mites. PKCλ/ι-deficiency significantly inhibited airway inflammations. The infiltrating cells in the lungs and bronchoalveolar lavage fluids were significantly reduced in conditional PKCλ/ι-deficient mice. Th17 effector cytokines were reduced in the bronchoalveolar lavage fluids and lungs at protein and mRNA levels. Thus, PKCλ/ι emerges as a critical regulator of Th17 differentiation and allergic airway hyperresponsiveness. Graphical abstract
    Print ISSN: 0925-4439
    Electronic ISSN: 1879-260X
    Topics: Biology , Chemistry and Pharmacology , Medicine , Physics
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  • 33
    Publication Date: 2018-01-04
    Description: Publication date: Available online 3 January 2018 Source: Biochemical Pharmacology Author(s): Suyan Li, Yota Uno, Uwe Rudolph, Johanna Cobb, Jing Liu, Thea Anderson, Deborah Levy, Darrick T. Balu, Joseph T. Coyle D-Serine is a co-agonist at forebrain N-methyl-D-aspartate receptors (NMDAR) and is synthesized by serine racemase (SR). Although D-serine and SR were originally reported to be localized to glia, recent studies have provided compelling evidence that under healthy physiologic conditions both are localized primarily in neurons. However, in pathologic conditions, reactive astrocytes can also express SR and synthesize D-serine. Since cultured astrocytes exhibit features of reactive astrocytes, we have characterized D-serine synthesis and the expression of enzymes involved in its disposition in primary glial cultures. The levels of SR were quite low early in culture and increased markedly in all astrocytes with the duration in vitro . The concentration of D-serine in the culture medium increased in parallel with SR expression in the astrocytes. Microglia, identified by robust expression of Iba1, did not express SR. While the levels of glial fibrillary acidic protein (GFAP), glycine decarboxylase (GLDC) and phosphoglycerate dehydrogenase (PHGDH), the initial enzyme in the pathway converting glycine to L-serine, remained constant in culture, the expression of lipocalin-2, a marker for pan-reactive astrocytes, increased several-fold. The cultured astrocytes also expressed Complement-3a, a marker for a subpopulation of reactive astrocytes (A1). Astrocytes grown from mice with a copy number variant associated with psychosis, which have four copies of the GLDC gene, showed a more rapid production of D-serine and a reduction of glycine in the culture medium. These results substantiate the conclusion that A1 reactive astrocytes express SR and release D-serine under pathologic conditions, which may contribute to their neurotoxic effects by activating extra-synaptic NMDARs. Graphical abstract
    Print ISSN: 0006-2952
    Electronic ISSN: 1873-2968
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 34
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    Publication Date: 2018-01-04
    Description: Publication date: Available online 3 January 2018 Source: Biochemical Pharmacology Author(s): Lizi Xia, Athina Kyrizaki, Dilip K. Tosh, Tirsa T. van Duijl, Jacomina Cornelia Roorda, Kenneth A. Jacobson, Adriaan P. IJzerman, Laura H. Heitman The human adenosine A 3 (hA 3 ) receptor has been suggested as a viable drug target in inflammatory diseases and in cancer. So far, a number of selective hA 3 receptor agonists (e.g. IB-MECA and 2-Cl-IB-MECA) inducing anti-inflammatory or anticancer effects are under clinical investigation. Drug-target binding kinetics is increasingly recognized as another pharmacological parameter, next to affinity, for compound triage in the early phases of drug discovery. However, such a kinetics-driven analysis has not yet been performed for the hA 3 receptor. In this study, we first validated a competition association assay for adenosine A 3 receptor agonists to determine the target interaction kinetics. Affinities and Kinetic Rate Index (KRI) values of 11 ribofurano and 10 methanocarba nucleosides were determined in radioligand binding assays. Afterwards, 15 analogues were further selected (KRI 〈0.70 or KRI >1.35) for full kinetics characterization. The structure-kinetics relationships (SKRs) were derived and longer residence times were associated with methanocarba and enlarged adenine N 6 and C2 substitutions. In addition, from a k on -k off -K D kinetic map we divided the agonists into three subgroups. A residence time “cliff” was observed, which might be relevant to (N)-methanocarba derivatives’ rigid C2-arylalkynyl substitutions. Our findings provide substantial evidence that, next to affinity, additional knowledge of binding kinetics is useful for developing and selecting new hA 3 R agonists in the early phase of the drug discovery process. Graphical abstract
    Print ISSN: 0006-2952
    Electronic ISSN: 1873-2968
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 35
    Publication Date: 2018-01-04
    Description: Publication date: Available online 3 January 2018 Source: Leukemia Research Author(s): Junko Okabe-Kado, Yuki Hagiwara-Watanabe, Nozomi Niitsu, Takashi Kasukabe, Yasuhiko Kaneko The NM23 gene is overexpressed in many hematological malignancies and its overexpression predicts poor treatment outcomes. NM23 overexpression is thought to suppress myeloid differentiation of leukemia cells, but the molecular mechanism is unknown. In breast cancer cells, the lysophosphatidic acid (LPA) receptor EDG2/ lpa1 was downregulated by NM23-H1 overexpression, and this reciprocal expression pattern was associated with suppressed or induced cell motility/metastasis. Here, we examined the relationship between EDG2 and NM23 expression during myeloid differentiation of leukemia cells. NM23 expression decreased and EDG2 expression increased during all-trans retinoic acid (ATRA)-induced myeloid differentiation of HL-60, NB4, and THP-1 leukemia cells. Moreover, this inverse correlation was more evident when myeloid differentiation was enhanced by ellagic acid, an inhibitor of NM23 activity. In contrast, there was no inverse correlation between EDG2 and NM23 expression during erythroid differentiation of HEL and K562 cells. ATRA plus LPA enhanced the motility of leukemia cells as well as breast cancer cells in an EDG2-dependent manner. These results suggest a common molecular mechanism between myeloid differentiation of leukemia cells and migration of breast cancer cells depending on NM23 and EDG2 expression levels. Graphical abstract
    Print ISSN: 0145-2126
    Electronic ISSN: 1873-5835
    Topics: Medicine
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  • 36
    Publication Date: 2018-01-04
    Description: Publication date: Available online 2 January 2018 Source: Leukemia Research Author(s): Natalia C. Millan, Analía Pastrana, Myriam R. Guitter, Pedro A. Zubizarreta, María S. Monges, María S. Felice Eighty percent of children with acute lymphoblastic leukemia (ALL) survive with current treatments. Neurotoxicity is an infrequent adverse event. We describe clinical presentations of neurological toxicity, phases of treatment when these adverse events were more frequent and patients ́ outcome. From January-1995 to December-2015, 1,379 ALL cases were admitted. Neurotoxicity was diagnosed in 49 patients (3.6%) and classified according to neurological syndromes. Medical records, laboratory-tests and images were reviewed. The diagnosed syndromes were: a) Methotrexate-leukoencephalopathy (MLE) (35.4%); b) Cerebral-venous-sinus thrombosis following L-Asparaginase administration (26.5%); c) Vincristine-induced-vocal-cord paralysis (VVCP) (14.2%); d) Stroke-associated vasospasm (14%), after high-dose methotrexate e) Severe polyneuropathy (6.1%); f) Methotrexate myelopathy (2%); and g) Pseudotumor-cerebri (2%) associated with corticosteroid therapy. Neurotoxicity was diagnosed during induction in 55% of cases. We conclude that MLE was the most frequent syndrome. VVCP was observed in infants and Down patients. Seizure was the most common symptom and toxicity occurred mainly during induction phase.
    Print ISSN: 0145-2126
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  • 37
    Publication Date: 2018-01-04
    Description: Publication date: Available online 3 January 2018 Source: Magnetic Resonance Imaging Author(s): Alexander Adair, Igor V. Mastikhin, Benedict Newling The pressure variations experienced by a liquid flowing through a pipe constriction can, in some cases, result in the formation of a bubble cloud (i.e., hydrodynamic cavitation). Due to the nature of the bubble cloud, it is ideally measured through the use of non-optical and non-invasive techniques; therefore, it is well-suited for study by magnetic resonance imaging. This paper demonstrates the use of Conical SPRITE (a 3D, centric-scan, pure phase-encoding pulse sequence) to acquire time-averaged void fraction and velocity information about hydrodynamic cavitation for water flowing through a pipe constriction.
    Print ISSN: 0730-725X
    Electronic ISSN: 1873-5894
    Topics: Medicine
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  • 38
    Publication Date: 2018-01-04
    Description: Publication date: Available online 3 January 2018 Source: Magnetic Resonance Imaging Author(s): Daniel V. Olson, Volkan Arpinar, L. Tugan Muftuler Purpose Diffusion kurtosis imaging (DKI) has gained popularity in recent years as an advanced diffusion-weighted MRI technique. This work aims to quantitatively compare the performance and accuracy of four DKI processing algorithms. For this purpose, a digital DKI brain phantom is developed. Methods Data from the Human Connectome Project database were used to generate a DKI digital phantom. In a Monte Carlo Rician noise simulation, four DKI processing algorithms were compared based on their mean square error, squared bias, and variance. Results Algorithm performance was region-dependent and differed for each diffusion metric and noise level. Crossover between variance and squared bias error occurred between signal-to-noise ratios of 30 and 40. Conclusion Through the framework presented here, DKI algorithms can be quantitatively compared via a ground truth data set. Error maps are critical as algorithm performance varies spatially. Bias-plus-variance decomposition provides a more complete picture than MSE alone. In combination with refinements in acquisition in future studies, the accuracy and efficiency of DKI will continue to improve promoting clinical adoption.
    Print ISSN: 0730-725X
    Electronic ISSN: 1873-5894
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  • 39
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    Elsevier
    Publication Date: 2018-01-04
    Description: Publication date: Available online 3 January 2018 Source: Magnetic Resonance Imaging Author(s): R. Acquaviva, S. Mangione, G. Garbo In order to reduce geometric distortion phenomena in MR images, every MRI system main magnet undergoes a shimming process. Since this process aims at optimizing magnetic field homogeneity within a so-called uniformity sphere, image quality outside this sphere is neglected. Since the fields vary smoothly in space, MR signal-to-noise ratio is still non-zero just outside the uniformity region, but correction of MR image distortion fails due to lack of magnetic field knowledge outside it. We propose a novel algorithm for measuring all the fields involved in the generation of images. Our proposal is based on exploitation of the distortion which can be observed in images of a known phantom. The proposed method will enable measurement of the fields in a region that can be bigger than the uniformity sphere depending on the phantom dimensions.
    Print ISSN: 0730-725X
    Electronic ISSN: 1873-5894
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  • 40
    Publication Date: 2018-01-04
    Description: Publication date: Available online 3 January 2018 Source: Protein Expression and Purification Author(s): Xiao-Dong Song, Chen-Jian Liu, Shi-Hao Huang, Xiao-Ran Li, En Yang, Yi-Yong Luo Quorum sensing (QS) is a means of cell-to-cell communication that regulates, via small signalling molecules, expression of a series of genes and controls multicellular behaviour in many bacterial species. The enzyme S-ribosylhomocysteine lyase (LuxS) transforms S-ribosylhomocysteine (SRH) into 4, 5-dihydroxy-2, 3-pentanedione (DPD), the precursor of the interspecies QS signalling molecule autoinducer-2 (AI-2). In this study, two LuxS-coding genes, luxS1 and luxS2 , with 70% sequence identity were isolated from Lactobacillus plantarum YM-4-3, and overexpressed in Escherichia coli BL21 (DE3), and the protein products were purified successfully. After incubation of LuxS1 or LuxS2 with SRH, the reaction products were able to induce Vibrio harveyi BB170 bioluminescence, clearly demonstrating that both LuxS1 and LuxS2 synthesize AI-2 from SRH in vitro . Ellman's assay results revealed optimal temperatures for LuxS1 and LuxS2 of 45 and 37 °C, respectively, and their activities were stimulated or inhibited by several metal ions and chemical reagents. In addition, enzyme kinetics data showed that K m , V max and K cat value of LuxS1 for the substrate (SRH) were higher than that of LuxS2. These results suggest that LuxS1 and LuxS2 mediate QS in a temperature-dependent manner and may play conserved roles in AI-2 synthesis but exhibit different activities in response to external environmental stress. To our knowledge, this paper is the first report of two luxS genes present in one bacterial genome and the subsequent comparative elucidation of their functions in AI-2 production. Collectively, our study provides a solid basis for future research concerning the AI-2/LuxS QS system in L. plantarum YM-4-3.
    Print ISSN: 1046-5928
    Electronic ISSN: 1096-0279
    Topics: Biology , Medicine
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  • 41
    Publication Date: 2018-01-04
    Description: Publication date: Available online 3 January 2018 Source: Gastroenterology Author(s): Joel Richter, Ambuj Kumar, Seth Lipka, Branko Miladinovic, Vic Velanovich Background & Aims The effects of transoral incisionless fundoplication (TIF) and laparoscopic Nissen fundoplication (LNF) have been compared with those of proton pump inhibitors (PPIs) or a sham procedure in patients with gastroesophageal reflux disease (GERD), but there has been no direct comparison of TIF vs LNF. We performed a systematic review and network meta-analysis of randomized controlled trials to compare the relative efficacies of TIF vs LNF in patients with GERD. Methods We searched publication databases and conference abstracts through May 10, 2017 for randomized controlled trials that compared the efficacy of TIF or LNF with that of a sham procedure or PPIs in patients with GERD. We performed a network meta-analysis using Bayesian methods under random-effects multiple treatment comparisons. We assessed ranking probability by surface under the cumulative ranking curve. Results Our search identified 7 trials comprising 1128 patients. Surface under the cumulative ranking curve ranking indicated TIF had highest probability of increasing patients’ health-related quality of life (HRQOL; 0.96), followed by LNF (0.66), a sham procedure (0.35), and PPIs (0.042). LNF had the highest probability of increasing percent time at pH〈4 (0.99), followed by PPIs (0.64), TIF (0.32), and the sham procedure (0.05). LNF also had the highest probability of increasing LES pressure (0.78), followed by TIF (0.72) and PPIs (0.01). Patients who underwent the sham procedure had the had the highest probability for persistent esophagitis (0.74), followed by those receiving TIF (0.69), LNF (0.38), and PPIs (0.19). Meta-regression showed a shorter follow-up time as a significant confounder for the outcome of HRQOL in studies of TIF. Conclusions In a systematic review and network meta-analysis of trials of patients with GERD, we found LNF to have the greatest ability to improve physiologic parameters of GERD, including increased LES pressure and percent time a pH〈4. Although TIF produced the largest increase in HRQOL, this could be due to the shorter follow-up time of patients treated with TIF vs LNF or PPIs. TIF is a minimally invasive endoscopic procedure, yet based on evaluation of benefits vs risks, we do not recommend it as a long-term alternative to PPI or LNF treatment of GERD.
    Print ISSN: 0016-5085
    Electronic ISSN: 1528-0012
    Topics: Medicine
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  • 42
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    Publication Date: 2018-01-04
    Description: Publication date: Available online 3 January 2018 Source: Trends in Microbiology Author(s): Akbar Adjie Pratama, Jan Dirk van Elsas Bacteriophages are among the most abundant and diverse biological units in the biosphere. They have contributed to our understanding of the central dogma of biology and have been instrumental in the evolutionary success of bacterial pathogens. In contrast to our current understanding of marine viral communities, the soil virome and its function in terrestrial ecosystems has remained relatively understudied. Here, we examine, in a comparative fashion, the knowledge gathered from studies performed in soil versus marine settings. We address the information with respect to the abundance, diversity, ecological significance, and effects of, in particular, bacteriophages on their host’s evolutionary trajectories. We also identify the main challenges that soil virology faces and the studies that are required to accompany the current developments in marine settings.
    Print ISSN: 0966-842X
    Electronic ISSN: 1878-4380
    Topics: Biology
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  • 43
    Publication Date: 2018-01-05
    Description: Publication date: Available online 3 January 2018 Source: Analytical Biochemistry Author(s): Luciana Assis Gobo, Leandro Machado de Carvalho, Fernanda Temp, Carine Viana, Carlos Fernando Mello An analytical method utilizing liquid chromatography coupled to mass spectrometry with electrospray ionization has been developed for the identification of prostaglandins (PGs) in cerebral tissues. The five compounds identified (thromboxane B2, prostaglandin E2, prostaglandin D2, 6-keto-prostaglandin F1 alpha and prostaglandin F2 alpha) are cellular mediators of inflammation and are involved in a variety of physiological and pathological processes by acting on membrane receptors on the surfaces of target cells. The parameters of the electrospray ionization interface were optimized to obtain the highest possible sensitivity for all compounds studied. The limits of detection ranged from 0.25 to 1.09 μg L −1 , and the limits of quantification ranged from 0.83 to 3.64 μg L −1 . The method was validated and applied to samples of brain tissue from five mice. The sample concentrations of the four prostaglandins quantified ranged from 375 ȵg L −1 for prostaglandin E2 to 6602 μg L −1 for prostaglandin D2. An advantage of this work that should be emphasized is the fast response of the method, which allows to obtaining the lipid profile after a 3 min chromatographic run. Graphical abstract
    Print ISSN: 0003-2697
    Electronic ISSN: 1096-0309
    Topics: Biology , Chemistry and Pharmacology
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  • 44
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    Elsevier
    Publication Date: 2018-01-04
    Description: Publication date: January 2018 Source: Gynecologic Oncology, Volume 148, Issue 1 Author(s): Alexander Melamed, Alexi A. Wright
    Print ISSN: 0090-8258
    Electronic ISSN: 1095-6859
    Topics: Medicine
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  • 45
    Publication Date: 2018-01-04
    Description: Publication date: 10 March 2018 Source: Gene, Volume 646 Author(s): Qing Li, Hongdan Yang, Lin He, Qun Wang Spermatogenesis involves a series of process including exiting from the mitotic cell cycle, entry into meiosis, completion of complex differentiation programs, and producing spermatozoa. Expression of various genes in an ordered manner, and interactions between various genes and their protein products, primarily controlled at the post-transcriptional level with DEAD-box RNA helicases playing a crucial role in germ cell development, are required for production of fertile sperm. Many members of this family have been deeply studied in spermatogenesis, such as DDX3X, DDX25 and DDX4, but few data are available on DDX52. In this study, we analyzed the expression patterns of Es -DDX52, Es -DDX6, Es -Vasa and Es -XRN1 both at mRNA and protein levels in different tissues and during gonadal development. It showed that Es-vasa , Es-DDX6 and Es-Xrn1 , components of cytoplasmic foci P-bodies, have the similar transcriptional expression pattern, while Es-DDX52 has the reverse tendency. Furthermore, Es -DDX6 and Es -XRN1 proteins have the same localization in testicular tissues. Es -DDX52 mainly distributed in the cytoplasm of spermatogonia, only localized in the nucleus of early and middle spermatid and shifted to pre-acrosome vesicle (later developed into apical cap and acrosome tube) at both mRNA and protein levels. These results indicated that Es -DDX52 may participate in regulation of P-bodies and microtubules by Es -XRN1, and involved in the mitosis of spermatonia and spermatid differentiation.
    Print ISSN: 0378-1119
    Electronic ISSN: 1879-0038
    Topics: Biology
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  • 46
    Publication Date: 2018-01-04
    Description: Publication date: 10 March 2018 Source: Gene, Volume 646 Author(s): Xiabin Lan, Wei Sun, Wenwu Dong, Zhihong Wang, Ting Zhang, Liang He, Hao Zhang Recent studies have highlighted important roles for long noncoding RNAs (lncRNAs) during the complex process of carcinogenesis. H19 is an example of an lncRNA that can function either as a tumor promoter or a tumor suppressor. Here, we investigated the role of H19 in papillary thyroid carcinoma (PTC). First, we assessed H19 expression levels in human PTC tissues and PTC cell lines using quantitative real-time PCR. We also established H19-overexpressed PTC cell lines with lentiviral vectors to investigate the effects of H19 on the proliferation and migration of PTC cells. Our results suggest that H19 is downregulated in PTC tissues and in PTC cell lines compared to controls. Decreased H19 expression was correlated with lymph node metastasis. H19 overexpression reduced PTC cell proliferation and migration. It also inhibited the expression of tumor necrosis factor receptor 2. These results suggest that H19 inhibits tumorigenesis in PTC and may be utilized as a potential diagnostic tool for PTC.
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  • 47
    Publication Date: 2018-01-04
    Description: Publication date: January 2018 Source: Gynecologic Oncology, Volume 148, Issue 1 Author(s): Neil S. Horowitz, G. Larry Maxwell, Austin Miller, Chad A. Hamilton, Bunja Rungruang, Noah Rodriguez, Scott D. Richard, Thomas C. Krivak, Jeffrey M. Fowler, David G. Mutch, Linda Van Le, Roger B. Lee, Peter Argenta, David Bender, Krishnansu S. Tewari, David Gershenson, James J. Java, Michael A. Bookman Objective Microscopic residual disease following complete cytoreduction (R0) is associated with a significant survival benefit for patients with advanced epithelial ovarian cancer (EOC). Our objective was to develop a prediction model for R0 to support surgeons in their clinical care decisions. Methods Demographic, pathologic, surgical, and CA125 data were collected from GOG 182 records. Patients enrolled prior to September 1, 2003 were used for the training model while those enrolled after constituted the validation data set. Univariate analysis was performed to identify significant predictors of R0 and these variables were subsequently analyzed using multivariable regression. The regression model was reduced using backward selection and predictive accuracy was quantified using area under the receiver operating characteristic area under the curve (AUC) in both the training and the validation data sets. Results Of the 3882 patients enrolled in GOG 182, 1480 had complete clinical data available for the analysis. The training data set consisted of 1007 patients (234 with R0) while the validation set was comprised of 473 patients (122 with R0). The reduced multivariable regression model demonstrated several variables predictive of R0 at cytoreduction: Disease Score (DS) ( p 〈 0.001), stage ( p = 0.009), CA125 ( p 〈 0.001), ascites ( p 〈 0.001), and stage-age interaction ( p = 0.01). Applying the prediction model to the validation data resulted in an AUC of 0.73 (0.67 to 0.78, 95% CI). Inclusion of DS enhanced the model performance to an AUC of 0.83 (0.79 to 0.88, 95% CI). Conclusions We developed and validated a prediction model for R0 that offers improved performance over previously reported models for prediction of residual disease. The performance of the prediction model suggests additional factors (i.e. imaging, molecular profiling, etc.) should be explored in the future for a more clinically actionable tool.
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  • 48
    Publication Date: 2018-01-04
    Description: Publication date: January 2018 Source: Gynecologic Oncology, Volume 148, Issue 1 Author(s): Haley A. Moss, Laura J. Havrilesky Patient-reported outcomes (PRO) are defined as a report of a patient's symptoms, function and general well-being that comes directly from the patient, without interpretation of the response by a medical provider. As greater emphasis is placed on high-quality, patient-centered care, the importance of PROs has become widely accepted by policymakers, third party payers, medical societies, health care systems and clinical researchers. Despite increased recognition of the importance of PROs, they have not become a widely-implemented part of clinical care and their use in clinical research has been limited by methodological concerns. Health service researchers and providers are working to standardize and develop new methods to improve implementation of PROs in clinical and research settings. This article reviews the development of PRO measurement tools, implementation in the healthcare setting and relevance in clinical trials, with a focus on clinical care and research in gynecologic oncology.
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  • 49
    Publication Date: 2018-01-04
    Description: Publication date: January 2018 Source: Gynecologic Oncology, Volume 148, Issue 1 Author(s): Roberto Tozzi, Jvan Casarin, Riccardo Garruto-Campanile, Hooman Soleymani Majd, Matteo Morotti Objective To investigate the morbidity of diverting loop ileostomy (DLI) performed during Visceral Peritoneal Debulking (VPD) for stage IIIC-IV ovarian cancer and to report the rate, timing, and morbidity of DLI reversal. Methods We retrieved the data of all consecutive patients who underwent sigmoid-rectum resection (SRR) followed by DLI. Morbidity was defined as any surgical/medical complications clearly correlated to the DLI. The reversal rate of DLI was defined as the number of patients who had the continuity of the gastrointestinal tract restored in the study period. Finally, we recorded the timing and the morbidity of the reversal surgery. Factors associated with non-reversal of DLI were reported. Results In the study period (01/2010–09/2016), complete data were available for 47 patients. Stoma-related complications occurred in 22 patients (46.8%). Eight patients (17.0%) were readmitted within 30 days from surgery. Thirty-two patients (68.1%) had their stoma reversed. The primary cause of non-reversal was tumor recurrence/progression (7/15, 46.7%). Patient's age, length of hospitalization, complications after VPD were associated with non-reversal of DLI. The mean time from DLI formation to stoma reversal was 6 months (± 1.7). Post-reversal related complications occurred in 37.1% of the patients. Conclusions In our series, 31.9% of the patients with FIGO stage IIIC-IV ovarian cancer who underwent SRR and DLI did not have stoma reversal. Overall they had approximately 45% risk of stoma-related morbidity and 37% risk of morbidity related to the stoma reversal. This information should be part of the consulting process when preparing for debulking surgery, particularly in patients who are likely to need a bowel resection.
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  • 50
    Publication Date: 2018-01-04
    Description: Publication date: January 2018 Source: Gynecologic Oncology, Volume 148, Issue 1 Author(s): Sonia Guleria, Allan Jensen, Susanne K. Kjær Objective A growing number of studies suggest that some ovarian cancers can arise from benign and borderline ovarian tumors. However, studies on the association between benign and borderline ovarian tumors are lacking. We studied the overall- and histotype-specific risk of borderline ovarian tumors among women with a benign ovarian tumor. Methods This nationwide cohort study included all Danish women diagnosed with a benign ovarian tumor ( n = 139,466) during 1978–2012. The cohort was linked to the Danish Pathology Data Bank and standardized incidence ratios (SIR) with 95% confidence intervals (CI) were calculated. Results Women with benign ovarian tumors had increased risks for subsequent borderline ovarian tumors (SIR 1.62, 95% CI 1.43–1.82), and this applied to both serous (SIR 1.69, 95% CI 1.39–2.03) and mucinous (SIR 1.75, 95% CI 1.45–2.10) histotypes of borderline ovarian tumors. The risk for borderline ovarian tumors was primarily increased for women diagnosed with a benign ovarian tumor before 40 years of age. The risk remained increased up to 9 years after a benign ovarian tumor diagnosis. Finally, the associations did not change markedly when analyzed for the different histotypes of benign (solid and cystic tumors) and borderline (serous and mucinous tumors) ovarian tumors. Conclusions Women with benign ovarian tumors have a long-term increased risk for borderline ovarian tumors. However, as all associations in this study were only adjusted for age and calendar period of diagnosis, more studies that are able to adjust for additional potential confounding variables are required to further understand these associations.
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  • 51
    Publication Date: 2018-01-04
    Description: Publication date: January 2018 Source: Gynecologic Oncology, Volume 148, Issue 1 Author(s): V. Heinzelmann-Schwarz, A. Knipprath Mészaros, S. Stadlmann, F. Jacob, A. Schoetzau, K. Russell, M. Friedlander, G. Singer, M. Vetter Objectives Endocrine therapy is used as maintenance in estrogen receptor (ER) positive breast cancers and has been proposed in low-grade serous ovarian cancers (LGSOC). Here we examine a rationale for its use as maintenance in high-grade serous ovarian cancers (HGSOC). Methods We accessed the TCGA PANCAN dataset to evaluate the expression of ESR1 . ESR1 expression data on all cancers (n = 8901) and HGSOC (n = 527) were followed by investigation of ER expression via immunohistochemistry (IHC) (n = 4071). The same was performed in an independent cohort for matched primary and recurrent HGSOC (n = 80). Finally, newly diagnosed ER + HGSOC patients were offered a maintenance therapy with Letrozole. Results ESR1 was strongly expressed in similar levels in HGSOC as in breast cancer. We found a strong ER expression via IHC in both the primary and matched recurrent HGSOC, particularly in the Platinum-resistant subgroup. The additional use of Letrozole as maintenance treatment was associated with a significantly prolonged recurrence free interval (after 24 months 60% when taking Letrozole versus 38.5% in the control group; p = 0.035; RFS: IC 50 reached by one subject versus 13.2 months). This effect was also present in patients treated additionally with Bevacizumab; 20.8% of patients had no recurrence after 12 months compared to 87.5% when taking Letrozole in addition to Bevacizumab ( p = 0.026). Conclusions Primary HGSOC have a slightly higher ESR1 than and a similar ER expression breast cancer where aromatase inhibitor maintenance is routine for decades. Here we demonstrate evidence for the usefulness of Letrozole in HGSOC, particularly in patients with chemotherapy resistance or residual disease.
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  • 52
    Publication Date: 2018-01-04
    Description: Publication date: January 2018 Source: Gynecologic Oncology, Volume 148, Issue 1 Author(s): Yong Jae Lee, Young Shin Chung, Jung-Yun Lee, Eun Ji Nam, Sang Wun Kim, Sunghoon Kim, Young Tae Kim Objective To investigate the relationship of the time interval from the completion of neoadjuvant chemotherapy (NAC) to the initiation of postoperative adjuvant chemotherapy (POAC) with the survival outcomes in patients with ovarian cancer. Methods We retrospectively investigated 220 patients with pathologically confirmed epithelial ovarian cancer who received NAC at Yonsei Cancer Hospital between 2006 and 2016. The time interval was defined as the period from the completion of NAC, spanning interval debulking surgery (IDS), to the initiation of POAC. Results The median time interval was 42 (range 16–178) days; 103 patients (53.1%) received POAC within 42 days after NAC while 91 patients (46.9%) received it after 42 days. There were no significant differences in patient characteristics between these 2 groups. Kaplan-Meier analysis showed that patients with longer time intervals (> 42 days) had poorer progression-free survival and overall survival (P = 0.039 and 0.005, respectively). In the multivariate analysis, patients with longer time intervals had significantly poorer progression-free (hazard ratio, 1.41; 95% confidence interval, 0.98–2.03; not significant) and overall survivals (hazard ratio, 2.03; 95% confidence interval, 1.16–3.54). When the patients were categorized according to time interval quartiles (≤ 37, 38–42, 43–50, and > 50 days), longer time intervals were associated with higher risks of recurrence and death (P for trend: 0.006 and 〈 0.001, respectively). Conclusion The time interval from the completion of NAC to the initiation of POAC appears to influence survival. Efforts to reduce the time interval might improve the outcomes in ovarian cancer patients undergoing NAC.
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  • 53
    Publication Date: 2018-01-04
    Description: Publication date: January 2018 Source: Gynecologic Oncology, Volume 148, Issue 1 Author(s): Sarah J. Kitson, Jennifer Lindsay, Vanitha N. Sivalingam, Mark Lunt, Neil A.J. Ryan, Richard J. Edmondson, Martin K. Rutter, Emma J. Crosbie Background Cardiovascular disease is a major cause of death in endometrial cancer survivors. The aim of this study was to determine whether women newly diagnosed with endometrial cancer have a higher prevalence of cardiovascular risk factors than the general population. Methods The prevalence of adequately treated and unrecognized/inadequately treated cardiovascular risk factors and the corresponding 10-year cardiovascular risk by QRISK2 score was measured in 150 consecutive women undergoing primary treatment for endometrioid endometrial cancer in the North West of England, and 746 age and ethnicity-matched control women from the Health Survey for England 2014. Results Women with endometrial cancer had higher proportions of obesity (BMI ≥ 30 60.7% vs. 32.4%, p 〈 0.0001) and a preponderance of unrecognized and inadequately treated cardiovascular risk factors. Compared with controls, endometrial cancer cases had a higher prevalence of incident hyperglycemia (57.2% vs. 11.5%, p 〈 0.0001), total: HDL cholesterol ratio > 4.5 (26.7% vs. 13.7%, p 〈 0.0001), and were more likely to have three or more cardiovascular risk factors (22% vs. 6%, p 〈 0.0001). This equates to a higher 10-year cardiovascular risk (median QRISK2 score 12.6% vs. 8.8%, p 〈 0.0001). Optimization of risk factors would have a greater impact on absolute cardiovascular disease risk for cases than controls (QRISK2 score reduction 1.8% vs. 0.7%). Conclusions Women undergoing primary treatment for endometrial cancer have a higher prevalence of cardiovascular risk factors than women without the disease. Early identification and treatment of these risk factors could improve outcomes for endometrial cancer survivors.
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  • 54
    Publication Date: 2018-01-04
    Description: Publication date: January 2018 Source: Gynecologic Oncology, Volume 148, Issue 1 Author(s): Li Dong, Margaret Z. Wang, Xue-lian Zhao, Rui-mei Feng, Shang-ying Hu, Qian Zhang, Jennifer S. Smith, You-lin Qiao, Fang-hui Zhao Objective ASCCP cervical cancer screening guidelines recommend triaging high-risk human papillomavirus (hrHPV) positive women with cytology and genotyping, but cytology is often unavailable in resource-limited areas. We compared the long-term risk of cervical cancer and precancers among type-specific hrHPV-positive women triaged by viral load to cytology and visual inspection with acetic acid (VIA). Methods A cohort of 1742 Chinese women was screened with cytology, VIA, and Hybrid Capture 2 (HC2) test and followed for ten years. All HC2-positive samples were genotyped. Viral load was measured by HC2 relative light units/cutoff (RLU/CO). Ten-year cumulative incidence rate (CIR) of cervical intraepithelial neoplasia grade 2 or worse (CIN2 +) for type-specific hrHPV viral load was estimated using Kaplan-Meier methods. Results Baseline hrHPV viral load stratified by specific genotypes was positively correlated with prevalent cytological lesions. Ten-year CIR of CIN2 + was associated with cytological lesions and viral load. Among HPV 16/18-positive women, ten-year CIR of CIN2 + was high, even with normal cytology (15.3%), normal VIA (32.4%), viral load with RLU/CO 〈 10 (23.6%) or RLU/CO 〈 100 (33.8%). Among non-16/18 hrHPV positive women, ten-year CIR of CIN2 + was significantly stratified by cytology grade of atypical squamous cell of undetermined significance or higher (2.0% VS. 34.6%), viral load cutoffs at 10 RLU/CO (5.1% VS. 27.2%), at 100 RLU/CO (11.0% VS. 35.5%), but not by VIA (19.1% VS. 19.0%). Conclusions Our findings support the guidelines in referring all HPV16/18 positive women to colposcopy and suggest triaging non-16/18 hrHPV positive women using viral loads in resource-limited areas where cytology screening was inaccessible.
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  • 55
    Publication Date: 2018-01-04
    Description: Publication date: January 2018 Source: Heliyon, Volume 4, Issue 1 Author(s): Matilda Mali, Daniela Malcangio, Maria Michela Dell’ Anna, Leonardo Damiani, Piero Mastrorilli The environmental quality of Torre a Mare port (Italy) was assessed evaluating on one side, the chemical concentration of nine metals and metalloids within bottom sediments and on the other one, by exploring the impact of hydrodynamic conditions in contaminant’s transport within the most polluted basins. The investigated port was selected as case study because it resulted much more polluted than it was expected based on the touristic port activities and related stressors loading on it. In order to determine the origin and fate of contaminants in the port basin, 2D numerical simulations were carried out by MIKE21 software. The hydrodynamic module (HD) based on a rectangular grid was initially used to characterize the flow field into two domains that cover the inner and offshore harbor area. Then, advection–dispersion (AD) and water quality (WQ) modules were coupled in order to simulate the simultaneous processes of transport and dispersion of hypothetical pollutant sources. The dissolved/suspended sediment particulates (DSS) were selected as contaminant tracers. The comparative analysis between simulation responses and the real metal contaminant distribution showed high agreement, suggesting that contaminants mainly come from outside port and tend to accumulate in the inner basin. In fact, hydrodynamic circulations cause inflowing streams toward the harbor entrance and the particular port morphology hampers the exit of fine sediments from the inner basin, enhancing thus the accumulation of sediment-associated contaminants within the port area. The study confirms that the quality of touristic port areas strongly depends on both pollution sources located within and outside the port domain and it is controlled mainly by the hydrodynamic-driven processes.
    Electronic ISSN: 2405-8440
    Topics: Natural Sciences in General
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  • 56
    Publication Date: 2018-01-05
    Description: Publication date: 1 March 2018 Source: Gene, Volume 645 Author(s): Tianxiao Zhang, Liping Hou, David T. Chen, Francis J. McMahon, Jen-Chyong Wang, John P. Rice Bipolar disorder is a mental illness with lifetime prevalence of about 1%. Previous genetic studies have identified multiple chromosomal linkage regions and candidate genes that might be associated with bipolar disorder. The present study aimed to identify potential susceptibility variants for bipolar disorder using 6 related case samples from a four-generation family. A combination of exome sequencing and linkage analysis was performed to identify potential susceptibility variants for bipolar disorder. Our study identified a list of five potential candidate genes for bipolar disorder. Among these five genes, GRID1 (Glutamate Receptor Delta-1 Subunit), which was previously reported to be associated with several psychiatric disorders and brain related traits, is particularly interesting. Variants with functional significance in this gene were identified from two cousins in our bipolar disorder pedigree. Our findings suggest a potential role for these genes and the related rare variants in the onset and development of bipolar disorder in this one family. Additional research is needed to replicate these findings and evaluate their patho-biological significance.
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  • 57
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    Elsevier
    In: Gene
    Publication Date: 2018-01-05
    Description: Publication date: 10 March 2018 Source: Gene, Volume 646 Author(s): Meng-Ting Luo, Yu Fan, Dan Mu, Yong-Gang Yao, Yong-Tang Zheng The APOBEC3 family is a series antiviral factors that inhibit the replication of many viruses, such as HIV-1 and HBV. Tree shrews ( Tupaia belangeri ) possess great potential as an animal model for human diseases and therapeutic responses. However, the APOBEC3 family is unknown in tree shrews. Recent work has showed the presence of the APOBEC3 family in tree shrews. In this work, the cDNA sequences of five APOBEC3 members were identified in tree shrews, namely, tsAPOBEC3A , -3C , -3F , -3G and -3H . The results showed that their sequences encoded a zinc ( Z )-coordinating-domain as a characteristic of APOBEC3 proteins. Phylogenetic analysis revealed that the tree shrew APOBEC3 ( tsAPOBEC3 ) genes have occurred independently and that they are clustered with other mammalian APOBEC3 members. Transcript expression analysis indicated that tsAPOBEC3 genes are constitutively expressed, and high in immune-related tissues. tsAPOBEC3 gene expression was up-regulated in hepatocytes and PBMCs by IFN-α stimulation. Finally, tsAPOBEC3 proteins could edit both sides of DNA by inserting G → A and C → T hypermutations. Overall, the results suggest that the tsAPOBEC3 family could play a key role in defense immunity through distinct editing mechanisms. Our results provided insights into the genetic basis for the development of a tree shrew model for studying viral infection. Future studies will focus on deepening our understanding on the antiviral functions of these editing enzymes in tree shrew.
    Print ISSN: 0378-1119
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  • 58
    Publication Date: 2018-01-05
    Description: Publication date: 10 March 2018 Source: Gene, Volume 646 Author(s): Lirong Yao, Juncheng Wang, Baochun Li, Yaxiong Meng, Xiaole Ma, Erjing Si, Panrong Ren, Ke Yang, Xunwu Shang, Huajun Wang Although Halogeton glomeratus ( H . glomeratus ) has been confirmed to have a unique mechanism to regulate Na + efflux from the cytoplasm and compartmentalize Na + into leaf vacuoles, little is known about the salt tolerance mechanisms of roots under salinity stress. In the present study, transcripts were sequenced using the BGISEQ-500 sequencing platform (BGI, Wuhan, China). After quality control, approximately 24.08 million clean reads were obtained and the average mapping ratio to the reference gene was 70.00%. When comparing salt-treated samples with the control, a total of 550, 590, 1411 and 2063 DEIs were identified at 2, 6, 24 and 72 h, respectively. Numerous differentially-expressed isoforms that play important roles in response and adaptation to salt condition are related to metabolic processes, cellular processes, single-organism processes, localization, biological regulation, responses to stimulus, binding, catalytic activity and transporter activity. Fifty-eight salt-induced isoforms were common to different stages of salt stress; most of these DEIs were related to signal transduction and transporters, which maybe the core isoforms regulating Na + uptake and transport in the roots of H . glomeratus . The expression patterns of 18 DEIs that were detected by quantitative real-time polymerase chain reaction were consistent with their respective changes in transcript abundance as identified by RNA-Seq technology. The present study thoroughly explored potential isoforms involved in salt tolerance on H . glomeratus roots at five time points. Our results may serve as an important resource for the H . glomeratus research community, improving our understanding of salt tolerance in halophyte survival under high salinity stress.
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  • 59
    Publication Date: 2018-01-05
    Description: Publication date: March 2018 Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Volume 1864, Issue 3 Author(s): Massimo Santoro, Luana Fontana, Francesca Maiorca, Federica Centofanti, Roberto Massa, Gabriella Silvestri, Giuseppe Novelli, Annalisa Botta Myotonic Dystrophy type 2 (DM2) is a multisystemic disorder associated with an expanded [CCTG]n repeat in intron 1 of the CNBP gene. Epigenetic modifications have been reported in many repeat expansion disorders, including myotonic dystrophy type 1 (DM1), either as a mechanism to explain somatic repeat instability or transcriptional alterations in disease genes. The purpose of our work was to determine the effect of DM2 mutation on the methylation status of CpG islands localized in the 5′ promoter region and in the 3′ end of the [CCTG]n expansion of the CNBP gene. By bisulfite pyrosequencing, we characterized the methylation profile of two different CpG islands within these regions, either in whole blood and skeletal muscle tissues of DM2 patients ( n = 72 and n = 7, respectively) and controls ( n = 50 and n = 7, respectively). Moreover, we compared the relative mRNA transcript levels of CNBP gene in leukocytes and in skeletal muscle tissues from controls and DM2 patients. We found that CpG sites located in the promoter region showed hypomethylation, whereas CpG sites at 3′ end of the CCTG array are hypermethylated. Statistical analyses did not demonstrate any significant differences in the methylation profile between DM2 patients and controls in both tissues analyzed. According to the methylation analysis, CNBP gene expression levels are not significantly altered in DM2 patients. These results show that [CCTG]n repeat expansion, differently from the DM1 mutation, does not influence the methylation status of the CNBP gene and suggest that other molecular mechanisms are involved in the pathogenesis of DM2.
    Print ISSN: 0925-4439
    Electronic ISSN: 1879-260X
    Topics: Biology , Chemistry and Pharmacology , Medicine , Physics
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  • 60
    Publication Date: 2018-01-05
    Description: Publication date: Available online 4 January 2018 Source: International Journal of Radiation Oncology*Biology*Physics Author(s): Andre Bongers, Eric Hau, Han Shen Purpose Diffusion weighted Imaging (DWI) is a promising microstructural modality for early detection of radiation treatment effects on a cellular level. However, standard clinical DWI protocols are often too insensitive as reliable radiation biomarker. Based on the hypothesis that sensitivity of clinical pulsed gradient DWI protocols (PGSE) may be impacted by their typically long effective diffusion-times (Δ eff ), we investigate a novel alternative approach using oscillating gradients preparation (OGSE) to obtain much shorter Δ eff for tumor response monitoring by ADC mapping in a glioblastoma mouse model. Methods 24 BALB/c nude mice inoculated with U87 glioblastoma cells were randomized into a control and irradiation group, which underwent a 15-day fractioned RT course with 2Gy/d. Therapy response was assessed by mapping of apparent diffusion coefficients (ADC) at 6 time points using an in-house implementation of a cos-OGSE DWI sequence with Δ eff =1.25ms and compared with a standard PGSE with typical clinical diffusion time Δ eff =18ms. Longitudinal ADC changes in tumor and contralateral white matter (WM) were statistically assessed using repeated-measures ANOVA and post-hoc (Sidak) testing. Results On short Δ eff OGSE maps tumor ADC was generally 30-50% higher than in surrounding WM. Areas correlated well with histology. Tumor identification was generally more difficult on PGSE maps due to non-significant WM/tumor contrast. During RT, OGSE maps also showed significant tumor ADC increase (∼15%) in response to radiation, consistently seen after 14Gy RT-dose. The clinical reference (PGSE) showed lower sensitivity to radiation changes and no significant response across the radiation group and timecourse could be detected. Conclusion Our short Δ eff DWI method using OGSE better reflected histologically defined tumor areas and enabled more consistent and earlier detection of microstructural radiation changes than conventional methods. OGSE offers significant potential as a robust microstructural RT response biomarker potentially helping to shift important therapy decisions to earlier stages in the RT-timecourse. Teaser This study investigates DWI at very short diffusion times (Δ eff ) as a novel tool for radiotherapy monitoring and response detection in a glioblastoma mouse model. Using oscillating gradient diffusion MRI (OGSE) to overcome Δ eff limits in conventional DWI we show that ADC mapping at short Δ eff can detect radiation changes significantly earlier and more robustly than standard clinical DWI. We believe that short Δ eff DWI is highly promising for radiotherapy monitoring on a cellular level.
    Print ISSN: 0360-3016
    Electronic ISSN: 1879-355X
    Topics: Medicine
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  • 61
    Publication Date: 2018-01-05
    Description: Publication date: Available online 4 January 2018 Source: International Journal of Radiation Oncology*Biology*Physics Author(s): Kelly C. Younge, Robin B. Marsh, Dawn Owen, Huaizhi Geng, Ying Xiao, Daniel E. Spratt, Joseph Foy, Krithika Suresh, Q. Jackie Wu, Fang-Fang Yin, Samuel Ryu, Martha M. Matuszak Purpose Consistency and standardization of radiotherapy plan quality in multi-institutional clinical trials are always challenging, and non-protocol compliant radiotherapy plans have been shown to impact patient outcomes. This study aimed to use knowledge-based planning (KBP) as a method of producing high quality, consistent, protocol-compliant treatment plans, in a complex setting of spine SBRT on NRG Oncology RTOG 0631. Methods An internally developed KBP model was applied to an external validation cohort of 22 anonymized cases submitted under NRG Oncology RTOG 0631. The original and KBP plans were compared via their protocol compliance, target conformity and gradient index, dose to critical structures, and dose to surrounding normal tissues. Results The KBP model generated plans meeting all protocol objectives in a single optimization when tested on both internal and protocol-submitted NRG Oncology RTOG 0631 cases. Two submitted plans that were considered to have a protocol-unacceptable deviation were made protocol compliant through the use of the model. There were no statistically significant differences in protocol spinal cord metrics (D10% and D0.03cc) between the manually optimized plans and the KBP plans. The volume of PTV receiving prescription dose increased from 93.3 ± 3.2% to 98.3 ± 1.4% (P=0.01) when using KBP. High-dose spillage to surrounding normal tissues (V105%) showed no significant differences (2.1 ± 7.3 cc for manual plans to 1.8 ± 0.6 cc with KBP), and dosimetric outliers with large amounts of spillage were eliminated through the use of KBP. KBP plans were also found to be significantly more consistent in several metrics, including target coverage and high dose outside of the target. Conclusion Incorporation of KBP models into the clinical trial setting may have a profound impact on the quality of trial results due to the increase in consistency and standardization of planning, especially for treatment sites or techniques that are non-standard.
    Print ISSN: 0360-3016
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  • 62
    Publication Date: 2018-01-06
    Description: Publication date: 15 January 2018 Source: Experimental Cell Research, Volume 362, Issue 2 Author(s): Xiao Fang, Guojun Lu, Kyungsoo Ha, Han Lin, Ye Du, Qiuhong Zuo, Yi Fu, Chaoxia Zou, Pumin Zhang Tumor cells often encounter hypoglycemic microenvironment due to rapid cell expansion. It remains elusive how tumors reprogram the genome to survive the metabolic stress. The tumor suppressor TIP60 functions as the catalytic subunit of the human NuA4 histone acetyltransferase (HAT) multi-subunit complex and is involved in many different cellular processes including DNA damage response, cell growth and apoptosis. Attenuation of TIP60 expression has been detected in various tumor types. The function of TIP60 in tumor development has not been fully understood. Here we found that suppressing TIP60 inhibited p53 K120 acetylation and thus rescued apoptosis induced by glucose deprivation in hepatocellular cancer cells. Excitingly, Lys-104 (K104), a previously identified lysine acetylation site of TIP60 with unknown function, was observed to be indispensable for inducing p53-mediated apoptosis under low glucose condition. Mutation of Lys-104 to Arg (K104R) impeded the binding of TIP60 to human NuA4 complex, suppressed the acetyltransferase activity of TIP60, and inhibited the expression of pro-apoptotic genes including NOXA and PUMA upon glucose starvation. These findings demonstrate the critical regulation of TIP60/p53 pathway in apoptosis upon metabolic stress and provide a novel insight into the down-regulation of TIP60 in tumor cells. Graphical abstract
    Print ISSN: 0014-4827
    Electronic ISSN: 1090-2422
    Topics: Biology , Medicine
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  • 63
    Publication Date: 2018-01-06
    Description: Publication date: Available online 4 January 2018 Source: The International Journal of Biochemistry & Cell Biology Author(s): Ye-Li Zhao, Zhuo-Yu Lu, Xuan Zhang, Wei-Wei Liu, Guo-Dong Yao, Xiao-Ling Liu, Wei Liu, Qing-Jie Wu, Toshihiko Hayashi, Masayuki Yamato, Hitomi Fujisaki, Shunji Hattori, Yuji Atsuzawa, Shin-ichi Tashiro, Satoshi Onodera, Takashi Ikejima Gelatin, denatured collagen, temporarily exists in tissues and may well be pathophysiologically involved in tissue remodeling, inflammation or tissue damage. The present study is aimed to investigate possible biological roles of gelatin by examining its effects on monocyte-like histiocytic lymphoma cell line U937. Once stimulated by phorbol 12-myristate 13-acetate (PMA), U937 cells differentiate into macrophage-like cells, changing from non-adherent to adherent cells with extended pseudopodia. Here we pre-treated the cell dishes with gelatin solution for cell culture. Interestingly, we found that PMA-stimulated U937 cells formed multicellular aggregates on gelatin-coated dishes, accompanying NF-κB-mediated production of pro-inflammatory cytokines, whereas cell aggregation was not detected on non-coated dishes. Moreover, differentiated U937 cells on gelatin-coated dishes showed increased autophagy level and endocytosis. Surprisingly, formation of multicellular aggregates and pro-inflammatory cytokine production were both attenuated by either down-regulation of autophagy with inhibitors, such as 3-methyladenine (3MA) or chloroquine (CQ), or repression of endocytosis with siRNA targeting Endo180. Moreover, autophagy was inhibited by si-Endo180, and endocytosis was suppressed by 3MA, suggesting a positive feedback loop between autophagy and endocytosis. The results revealed that gelatin-coating induced differentiated U937 cells to form cell aggregates and promote NF-κB-mediated pro-inflammatory cytokine production at least partially through an endocytosis-autophagy pathway.
    Print ISSN: 1357-2725
    Electronic ISSN: 1878-5875
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 64
    Publication Date: 2018-01-06
    Description: Publication date: 1 March 2018 Source: Analytical Biochemistry, Volume 544 Author(s): Thuy Nguyen Thi Dao, Eun Yeong Lee, Bonhan Koo, Choong Eun Jin, Tae Yoon Lee, Yong Shin Rapid and sensitive detection of low amounts of pathogen in large samples is needed for early diagnosis and treatment of patients and surveillance of pathogen. In this study, we report a microfluidic platform for detection of low pathogen levels in a large sample volume that couples an Magainin 1 based microfluidic platform for pathogen enrichment and a recombinase polymerase amplification (RPA) sensor for simultaneous pathogenic DNA amplification and detection in a label-free and real-time manner. Magainin 1 is used as a pathogen enrichment agent with a herringbone microfluidic chip. Using this enrichment platform, the detection limit was found to be 20 times more sensitive in 10 ml urine with Salmonella and 10 times more sensitive in 10 ml urine with Brucella than that of real-time PCR without the enrichment process. Furthermore, the combination system of the enrichment platform and an RPA sensor that based on an isothermal DNA amplification method with rapidity and sensitivity for detection can detect a pathogen at down to 50 CFU in 10 ml urine for Salmonella and 10 2  CFU in 10 ml urine for Brucella within 60 min. This system will be useful as it has the potential for better diagnosis of pathogens by increasing the capture efficiency of the pathogen in large samples, subsequently enhancing the detection limit of pathogenic DNA.
    Print ISSN: 0003-2697
    Electronic ISSN: 1096-0309
    Topics: Biology , Chemistry and Pharmacology
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  • 65
    Publication Date: 2018-01-06
    Description: Publication date: Available online 5 January 2018 Source: Biochemical Pharmacology Author(s): Ana Lia Mazzeti, Lívia de F. Diniz, Karolina R. Gonçalves, Alvaro F.S. Nascimento, Pollyanna A.F. Spósito, Vanessa C.F. Mosqueira, George L.L. Machado-Coelho, Isabela Ribeiro, Maria T. Bahia Benznidazole and nifurtimox-treatments regimens currently used in human are supported by very limited experimental data. This study was designed to evaluate the time and dose dependence for efficacy of the most important nitroheterocyclic drugs in use for Chagas disease. In order to evaluate time dependence, Y strain-infected mice received benznidazole for a total of 1, 3, 7, 10, 20, and 40 days. Treatment courses of 3 to 10-day were effective in clearing parasitaemia and suppressing mortality, but parasitological cure was not achieved. Extending the treatments to 20 or 40 days clearly improved benznidazole efficacy. The 20-day treatment induced cure in 57.1% of Y strain infections (partially drug resistant) but failed to cure Colombian strain infections (full drug resistant), while the 40-day treatment resulted in cure of 100% of Y and 50% of Colombian strain infected mice. The increased cure rates in T. cruzi infected animals that received nifurtimox for 40 days confirm the relationship between the length of treatment and efficacy. An improvement in efficacy was observed with increasing benznidazole doses; cure was verified in 28.6% (75 mg/kg), 57.1% (100 mg/kg) and 80% (300 mg/kg). Overall, these nonclinical study data provide evidence that the efficacy of benznidazole is dose and time dependent. These findings may be relevant for optimizing treatment of human Chagas disease. Graphical abstract
    Print ISSN: 0006-2952
    Electronic ISSN: 1873-2968
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 66
    Publication Date: 2018-01-06
    Description: Publication date: Available online 5 January 2018 Source: Biochemical Pharmacology Author(s): Harald Braun, Inna S. Afonina, Christina Mueller, Rudi Beyaert Interleukin (IL)-33 is a cytokine that is released from epithelial and endothelial cells at barrier surfaces upon tissue stress or damage to operate as an alarmin. IL-33 has been primarily implicated in the induction of T helper (Th) 2 type immune responses. Therefore, IL-33 has attracted a lot of interest as a potential therapeutic target in asthma and other allergic diseases. Over the years, it has become clear that IL-33 has a much broader activity and also contributes to Th1 immunity, expanding the possibilities for therapeutic modulation of IL-33 activity to multiple inflammatory diseases. However, more recently IL-33 has also been shown to mediate immunosuppression and tissue repair by activating regulatory T cells (Treg) and promoting M2 macrophage polarization. These pleiotropic activities of IL-33 illustrate the need for a tight molecular regulation of IL-33 activity, and have to be taken into account when IL-33 or its receptor are targeted for therapeutic modulation. Here we review the multiple molecular mechanisms that regulate IL-33 activity and describe how IL-33 can shape innate and adaptive immune responses by promoting Th1, Th2 and Treg function. Finally, we will discuss the possibilities for therapeutic modulation of IL-33 signaling as well as possible safety issues. Graphical abstract
    Print ISSN: 0006-2952
    Electronic ISSN: 1873-2968
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 67
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    Elsevier
    Publication Date: 2018-01-06
    Description: Publication date: Available online 5 January 2018 Source: Biochemical Pharmacology Author(s): Jeannette M. Osterloh, Kevin Mullane Biomedical research is being transformed by the discovery and use of human pluripotent stem cells (hPSCs). Remarkable progress has been made, and assorted clinical trials are underway related to the application of stem cell therapy, including transplantation of hPSC-derived cells, in situ reprogramming or transdifferentiation, and utilization of targets and compounds identified from patient-derived stem cells. However, the pace of discovery is overwhelming efforts to replicate the work of others, prompting a concern over validity and reproducibility. Here, we address some sources of variability in reprogramming, maintaining, and differentiating hPSCs that impact interpretation of studies involving their use, and how it relates to efforts to move the field forward. The commitment in time and resources required to generate and maintain cell-lines, coupled with marked variations between hPSCs derived from patients with the same disease, has resulted in a fundamental change in how research is conducted. Dr. Michael Williams has championed the need to appropriately validate all cell-lines before use to limit sources of variability, although defining what constitutes a validated hPSC in the era of single cell –omics can be challenging. Graphical abstract
    Print ISSN: 0006-2952
    Electronic ISSN: 1873-2968
    Topics: Biology , Chemistry and Pharmacology , Medicine
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  • 68
    Publication Date: 2018-01-06
    Description: Publication date: March 2018 Source: Biochimica et Biophysica Acta (BBA) - Biomembranes, Volume 1860, Issue 3 Author(s): Victoria Schmidt, James N. Sturgis Recently, styrene-maleic acid copolymer lipid nanodiscs have become an increasingly popular tool for the study of membrane proteins. In the work we report here, we have developed a novel method for the efficient preparation of labeled nanodiscs, under chemically mild conditions, by modification of the hydrolyzed styrene-maleic acid copolymer. This protocol is designed to be easily accessible to biochemistry laboratories. We use this procedure to prepare various fluorescent nanodiscs labeled with different fluorophores. By studying the development of Förster resonance energy transfer, we demonstrate the rapid exchange of co-polymer between nanodiscs. This demonstration, in conjunction of previous work, indicates that the lipid nanodiscs prepared using this polymer are very dynamic structures with rapid exchange of the different components. Graphical abstract
    Print ISSN: 0005-2736
    Electronic ISSN: 1879-2642
    Topics: Biology , Chemistry and Pharmacology , Medicine , Physics
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  • 69
    Publication Date: 2018-01-06
    Description: Publication date: Available online 4 January 2018 Source: Current Biology Author(s): Allyson L. Anding, Chunxin Wang, Tsun-Kai Chang, Danielle A. Sliter, Christine M. Powers, Kay Hofmann, Richard J. Youle, Eric H. Baehrecke The clearance of mitochondria by autophagy, mitophagy, is important for cell and organism health [ 1 ], and known to be regulated by ubiquitin. During Drosophila intestine development, cells undergo a dramatic reduction in cell size and clearance of mitochondria that depends on autophagy, the E1 ubiquitin-activating enzyme Uba1, and ubiquitin [ 2 ]. Here we screen a collection of putative ubiquitin-binding domain-encoding genes for cell size reduction and autophagy phenotypes. We identify the endosomal sorting complex required for transport (ESCRT) components TSG101 and Vps36 , as well as the novel gene Vps13D . Vps13D is an essential gene that is necessary for autophagy, mitochondrial size, and mitochondrial clearance in Drosophila . Interestingly, a similar mitochondrial phenotype is observed in VPS13D mutant human cells. The ubiquitin-associated (UBA) domain of Vps13D binds K63 ubiquitin chains, and mutants lacking the UBA domain have defects in mitochondrial size and clearance and exhibit semi-lethality, highlighting the importance of Vps13D ubiquitin binding in both mitochondrial health and development. VPS13D mutant cells possess phosphorylated DRP1 and mitochondrial fission factor (MFF) as well as DRP1 association with mitochondria, suggesting that VPS13D functions downstream of these known regulators of mitochondrial fission. In addition, the large Vps13D mitochondrial and cell size phenotypes are suppressed by decreased mitochondrial fusion gene function. Thus, these results provide a previously unknown link between ubiquitin, mitochondrial size regulation, and autophagy. Graphical abstract Teaser Autophagy and mitochondrial clearance are important for cell health. Anding et al. identify Vps13D as a gene that is required for autophagy, mitochondrial size, and clearance in Drosophila , and human cells lacking VPS13D function have a similar mitochondrial size defect. Vps13D provides a unique link between mitochondrial size and autophagy.
    Print ISSN: 0960-9822
    Electronic ISSN: 1879-0445
    Topics: Biology
    Published by Elsevier on behalf of Cell Press.
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  • 70
    Publication Date: 2018-01-06
    Description: Publication date: Available online 4 January 2018 Source: Current Biology Author(s): Anja Günther, Angelika Einwich, Emil Sjulstok, Regina Feederle, Petra Bolte, Karl-Wilhelm Koch, Ilia A. Solov’yov, Henrik Mouritsen Birds seem to use a light-dependent, radical-pair-based magnetic compass. In vertebrates, cryptochromes are the only class of proteins that form radical pairs upon photo-excitation. Therefore, they are currently the only candidate proteins for light-dependent magnetoreception. Cryptochrome 4 (Cry4) is particularly interesting because it has only been found in vertebrates that use a magnetic compass. However, its structure and localization within the retina has remained unknown. Here, we sequenced night-migratory European robin ( Erithacus rubecula ) Cry4 from the retina and predicted the currently unresolved structure of the erCry4 protein, which suggests that erCry4 should bind Flavin. We also found that Cry1a , Cry1b , and Cry2 mRNA display robust circadian oscillation patterns, whereas Cry4 shows only a weak circadian oscillation. When we compared the relative mRNA expression levels of the cryptochromes during the spring and autumn migratory seasons relative to the non-migratory seasons in European robins and domestic chickens ( Gallus gallus ), the Cry4 mRNA expression level in European robin retinae, but not in chicken retinae, is significantly higher during the migratory season compared to the non-migratory seasons. Cry4 protein is specifically expressed in the outer segments of the double cones and long-wavelength single cones in European robins and chickens. A localization of Cry4 in double cones seems to be ideal for light-dependent magnetoreception. Considering all of the data presented here, especially including its localization within the European robin retina, its likely binding of Flavin, and its increased expression during the migratory season in the migratory bird but not in chicken, Cry4 could be the magnetoreceptive protein. Teaser Günther et al. suggest that Cry4 could be the magnetoreceptive protein in night-migratory songbirds. Cry4 seems to bind Flavin, shows only weak circadian oscillations, is specifically located in double cones and long-wavelength single cones, and is upregulated during the migratory season in night-migratory European robins but not in chicken.
    Print ISSN: 0960-9822
    Electronic ISSN: 1879-0445
    Topics: Biology
    Published by Elsevier on behalf of Cell Press.
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  • 71
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    Elsevier
    Publication Date: 2018-01-06
    Description: Publication date: Available online 5 January 2018 Source: Gynecologic Oncology Author(s): Barenya Mukerji, Caitlin Baptiste, Ling Chen, Ana I. Tergas, June Y. Hou, Cande V. Ananth, Alfred I. Neugut, Dawn L. Hershman, Jason D. Wright Objective Although racial disparities in treatment and outcome for endometrial cancer are well recognized, little work has explored disparities in young women. We performed a population-based analysis to compare survival between black and white women with endometrial cancer at 〈 50 years of age. Methods We used the National Cancer Data Base to identify women 〈 50 years of age with endometrial cancer from 1998 to 2012. Clinical and demographic characteristics were compared between black and white women and survival by race analyzed using Kaplan-Meier curves and multivariable Cox proportional hazards models. Results We identified a total of 35,850 women 〈 50 years of age including 31,947 (89.1%) white and 3903 (10.9%) black patients. Black women were more likely to have advanced stage, poorly differentiated, and non-endometrioid histology neoplasms ( P 〈 0.05 for all). In a multivariable model, survival was 19% worse for black patients than white patients (HR = 1.19; 95% CI, 1.08–1.32). A similar effect was seen when limited to women with early-stage tumors (HR = 1.24; 95% CI, 1.04–1.49), while among patients with advanced stage tumors, no association between race and survival was seen (HR = 1.12; 95% CI, 0.89–1.41). Five-year survival rates were 90.6% (95% CI, 88.6–92.3%) for white and 81.5% (95% CI, 73.0–87.5%) for black women with stage IB tumors, and 75.1% (95% CI, 72.5–77.5%) and 63.3% (95% CI, 54.1–71.2%) for white and black women with stage III tumors, respectively. Conclusions Young black women are more likely to present with pathologically aggressive, advanced stage tumors. Even after adjusting for these pathologic differences, young black women with endometrial cancer have higher mortality than white women.
    Print ISSN: 0090-8258
    Electronic ISSN: 1095-6859
    Topics: Medicine
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  • 72
    Publication Date: 2018-01-06
    Description: Publication date: 4 January 2018 Source: Molecular Cell, Volume 69, Issue 1 Author(s): Ryan Marshall, Colin S. Maxwell, Scott P. Collins, Thomas Jacobsen, Michelle L. Luo, Matthew B. Begemann, Benjamin N. Gray, Emma January, Anna Singer, Yonghua He, Chase L. Beisel, Vincent Noireaux CRISPR-Cas systems offer versatile technologies for genome engineering, yet their implementation has been outpaced by ongoing discoveries of new Cas nucleases and anti-CRISPR proteins. Here, we present the use of E. coli cell-free transcription-translation (TXTL) systems to vastly improve the speed and scalability of CRISPR characterization and validation. TXTL can express active CRISPR machinery from added plasmids and linear DNA, and TXTL can output quantitative dynamics of DNA cleavage and gene repression—all without protein purification or live cells. We used TXTL to measure the dynamics of DNA cleavage and gene repression for single- and multi-effector CRISPR nucleases, predict gene repression strength in E. coli , determine the specificities of 24 diverse anti-CRISPR proteins, and develop a fast and scalable screen for protospacer-adjacent motifs that was successfully applied to five uncharacterized Cpf1 nucleases. These examples underscore how TXTL can facilitate the characterization and application of CRISPR technologies across their many uses. Graphical abstract Teaser Marshall et al. demonstrate that an E. coli cell-free transcription-translation (TXTL) system can be used to improve the speed and scalability of characterizing CRISPR nucleases and their accessory factors. The method will facilitate the discovery of uncharacterized CRISPR nucleases and anti-CRISPR proteins and aid the validation of designed gRNAs.
    Print ISSN: 1097-2765
    Electronic ISSN: 1097-4164
    Topics: Biology , Medicine
    Published by Elsevier on behalf of Cell Press.
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  • 73
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    Elsevier
    Publication Date: 2018-01-06
    Description: Publication date: 2018 Source: Methods in Cell Biology, Volume 143
    Print ISSN: 0091-679X
    Topics: Biology , Medicine
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  • 74
    Publication Date: 2018-01-06
    Description: Publication date: February 2018 Source: European Journal of Cancer, Volume 90 Author(s): G.M. Haag, I. Zoernig, J.C. Hassel, N. Halama, J. Dick, N. Lang, L. Podola, J. Funk, C. Ziegelmeier, S. Juenger, M. Bucur, L. Umansky, C.S. Falk, A. Freitag, I. Karapanagiotou-Schenkel, P. Beckhove, A. Enk, D. Jaeger Background Immune checkpoint therapy has dramatically changed treatment options in patients with metastatic melanoma. However, a relevant part of patients still does not respond to treatment. Data regarding the prognostic or predictive significance of preexisting immune responses against tumour antigens are conflicting. Retrospective data suggested a higher clinical benefit of ipilimumab in melanoma patients with preexisting NY-ESO-1–specific immunity. Patients and methods Twenty-five patients with previously untreated or treated metastatic melanoma and preexisting humoural immune response against NY-ESO-1 received ipilimumab at a dose of 10 mg/kg in week 1, 4, 7, 10 followed by 3-month maintenance treatment for a maximum of 48 weeks. Primary endpoint was the disease control rate (irCR, irPR or irSD) according to immune-related response criteria (irRC). Secondary endpoints included the disease control rate according to RECIST criteria, progression-free survival and overall survival (OS). Humoural and cellular immune responses against NY-ESO-1 were analysed from blood samples. Results Disease control rate according to irRC was 52%, irPR was observed in 36% of patients. Progression-free survival according to irRC was 7.8 months, according to RECIST criteria it was 2.9 months. Median OS was 22.7 months; the corresponding 1-year survival rate was 66.8%. Treatment-related grade 3 AEs occurred in 36% with no grade 4–5 AEs. No clear association was found between the presence of NY-ESO-1–specific cellular or humoural immune responses and clinical activity. Conclusion Ipilimumab demonstrated clinically relevant activity within this biomarker-defined population. NY-ESO-1 positivity, as a surrogate for a preexisting immune response against tumour antigens, might help identifying patients with a superior outcome from immune checkpoint blockade. Clinical trial information: NCT01216696
    Print ISSN: 0959-8049
    Electronic ISSN: 1879-0852
    Topics: Medicine
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  • 75
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    Elsevier
    Publication Date: 2018-01-06
    Description: Publication date: January 2018 Source: Journal of Dermatological Science, Volume 89, Issue 1
    Print ISSN: 0923-1811
    Electronic ISSN: 1873-569X
    Topics: Medicine
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  • 76
    Publication Date: 2018-01-06
    Description: Publication date: January 2018 Source: Journal of Dermatological Science, Volume 89, Issue 1 Author(s): Ha-Jung Kim, Seung-Hwa Lee, Han-Na Go, Jae-Rin Ahn, Hye-Jung Kim, Soo-Jong Hong Background Atopic dermatitis (AD) is recently increasing among populations, but the underlying mechanisms remain controversial. Interactions between the gut microbiota and mucosal immunity are considered to be a crucial etiology. Fructooligosaccharide (FOS), prebiotics have been reported as activators of the gut microbiota. Objective The aim of this study was to investigate the effects of kestose, the smallest FOS and FOS on atopic dermatitis in mice. Methods An AD mouse model was developed by (ovalbumin) epidermal sensitization using BALB/c mice. Kestose (1%, 5%, and 10%) or FOS (5%, positive control) was orally administered throughout the study. Results In comparison with the values observed for the control AD mice, transepidermal water loss (TEWL), clinical score, and skin inflammation on histopathology were significantly decreased by the oral administration of kestose. Total IgE, thymic stromal lymphopoietin (TSLP) in skin, and IL-4 were also suppressed by this administration. In addition, the population of CD4 + Foxp3 + cells in mesenteric lymph nodes (MLNs) and acetate concentrations in feces were significantly increased by kestose treatment. Conclusions These findings suggest that kestose activates the gut immune system to induce the tolerance against allergic skin inflammations in AD.
    Print ISSN: 0923-1811
    Electronic ISSN: 1873-569X
    Topics: Medicine
    Published by Elsevier
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