The Value of a Closer Look

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Traitement endoscopique des carcinomes épidermoïdes superficiels de l’œsophage

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Exploring an adapted Risk Behaviour Diagnosis Scale among Indigenous Australian women who had experiences of smoking during pregnancy: a cross-sectional survey in regional New South Wales, Australia

Objectives

Explore Aboriginal women’s responses to an adapted Risk Behaviour Diagnosis (RBD) Scale about smoking in pregnancy.

Methods and design

An Aboriginal researcher interviewed women and completed a cross-sectional survey including 20 Likert scales.

Setting

Aboriginal Community Controlled Health Services, community groups and playgroups and Aboriginal Maternity Services in regional New South Wales, Australia.

Participants

Aboriginal women (n=20) who were pregnant or gave birth in the preceding 18 months; included if they had experiences of smoking or quitting during pregnancy.

Primary and secondary outcome measures

Primary outcomes: RBD constructs of perceived threat and perceived efficacy, dichotomised into high versus low. Women who had quit smoking, answered retrospectively. Secondary outcome measures: smoking status, intentions to quit smoking (danger control), protection responses (to babies/others) and fear control responses (denial/refutation). Scales were assessed for internal consistency. A chart plotted responses from low to high efficacy and low to high threat.

Results

RBD Scales had moderate-to-good consistency (0.67–0.89 Cronbach’s alpha). Nine women had quit and 11 were smoking; 6 currently pregnant and 14 recently pregnant. Mean efficacy level 3.9 (SD=0.7); mean threat 4.3 (SD=0.7). On inspection, a scatter plot revealed a cluster of 12 women in the high efficacy-high threat quadrant—of these 11 had quit or had a high intention of quitting. Conversely, a group with low threat-low efficacy (5 women) were all smokers and had high fear control responses: of these, 4 had low protection responses. Pregnant women had a non-significant trend for higher threat and lower efficacy, than those previously pregnant.

Conclusion

Findings were consistent with a previously validated RBD Scale showing Aboriginal smokers with high efficacy-high threat had greater intentions to quit smoking. The RBD Scale could have diagnostic potential to tailor health messages. Longitudinal research required with a larger sample to explore associations with the RBD Scale and quitting.

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Healthcare costs of asthma comorbidities: a systematic review protocol

Introduction

Asthma is associated with many comorbid conditions that have the potential to impact on its management, control and outcomes. These comorbid conditions have the potential to impact on healthcare expenditure. We plan to undertake a systematic review to synthesise the evidence on the healthcare costs associated with asthma comorbidity.

Methods and analysis

We will systematically search the following electronic databases between January 2000 and January 2017: National Health Service (NHS) Economic Evaluation Database, Google Scholar, Allied and Complementary Medicine Database (AMED), Global Health, PsychINFO, Medline, Embase, Institute for Scientific Information Web of Science and Cumulative Index to Nursing and Allied Health Literature. We will search the references in the identified studies for additional potential papers. Additional literature will be identified by contacting experts in the field and through searching of registers of ongoing studies. The review will include cost-effectiveness and economic modelling/evaluation studies and analytical observational epidemiology studies that have investigated the healthcare costs of asthma comorbidity. Two reviewers will independently screen studies and extract relevant data from included studies. Methodological quality of epidemiological studies will be assessed using the Effective Public Health Practice Project tool, while that of economic evaluation studies will be assessed using the Drummond checklist. This protocol has been published in International Prospective Register of Systematic Reviews (PROSPERO) database (No. CRD42016051005).

Ethics and dissemination

As there are no primary data collected, formal NHS ethical review is not necessary. The findings of this systematic review will be disseminated in a peer-reviewed journal and presented at relevant conferences.

PROSPEROregistration number

CRD42016051005.

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Physical pain is common and associated with nonmedical prescription opioid use among people who inject drugs

People who inject drugs (PWID) often have poor health and lack access to health care. The aim of this study was to examine whether PWID engage in self-treatment through nonmedical prescription opioid use (NMPO...

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Gender differences in discharge dispositions of emergency department visits involving drug misuse and abuse—2004-2011

Drug use-related visits to the emergency department (ED) can undermine discharge planning and lead to recurrent use of acute services. Yet, little is known about where patients go post discharge. We explored t...

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Structural Basis for Regulation of ESCRT-III Complexes by Lgd

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Brian J. McMillan, Christine Tibbe, Andrew A. Drabek, Tom C.M. Seegar, Stephen C. Blacklow, Thomas Klein
The ESCRT-III complex induces outward membrane budding and fission through homotypic polymerization of its core component Shrub/CHMP4B. Shrub activity is regulated by its direct interaction with a protein called Lgd in flies, or CC2D1A or B in humans. Here, we report the structural basis for this interaction and propose a mechanism for regulation of polymer assembly. The isolated third DM14 repeat of Lgd binds Shrub, and an Lgd fragment containing only this DM14 repeat and its C-terminal C2 domain is sufficient for in vivo function. The DM14 domain forms a helical hairpin with a conserved, positively charged tip, that, in the structure of a DM14 domain-Shrub complex, occupies a negatively charged surface of Shrub that is otherwise used for homopolymerization. Lgd mutations at this interface disrupt its function in flies, confirming functional importance. Together, these data argue that Lgd regulates ESCRT activity by controlling access to the Shrub self-assembly surface.

Graphical abstract

Teaser

Shrub is a Drosophila ESCRT-III protein that self-associates to promote membrane budding and fission. Its activity is modulated by binding to Lgd, which suppresses self-association. McMillan et al. report the structural basis for masking of the Shrub self-association surface of Shrub by Lgd, which, together with functional studies in flies, suggests models for modulation of Shrub activity by Lgd.


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The Histone Variant MacroH2A1 Is a BRCA1 Ubiquitin Ligase Substrate

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Beom-Jun Kim, Doug W. Chan, Sung Yun Jung, Yue Chen, Jun Qin, Yi Wang
The breast- and ovarian-cancer-specific tumor suppressor BRCA1 and its heterodimeric partner BARD1 contain RING domains that implicate them as E3 ubiquitin ligases. Despite extensive efforts, the bona fide substrates of BRCA1/BARD1 remain elusive. Here, we used recombinant GST fused to four UBA domains to enrich ubiquitinated proteins followed by a Lys-ε-Gly-Gly (diGly) antibody to enrich ubiquitinated tryptic peptides. This tandem affinity purification method coupled with mass spectrometry identified 101 putative BRCA1/BARD1 E3 substrates. We identified the histone variant macroH2A1 from the screen and showed that BRCA1/BARD1 ubiquitinates macroH2A1 at lysine 123 in vitro and in vivo. Primary human fibroblasts stably expressing a ubiquitination-deficient macroH2A1 mutant were defective in cellular senescence compared to their wild-type counterpart. Our study demonstrates that BRCA1/BARD1 is a macroH2A1 E3 ligase and implicates a role for macroH2A1 K123 ubiquitination in cellular senescence.

Graphical abstract

Teaser

Using a tandem affinity purification method coupled with mass spectrometry, Kim et al. identified 101 putative substrates of the BRCA1/BARD1 E3 ubiquitin ligase. They report that, among these substrates, ubiquitination at Lys123 of macroH2A1 plays an important role in replicative senescence.


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Synaptic Remodeling Depends on Signaling between Serotonin Receptors and the Extracellular Matrix

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Monika Bijata, Josephine Labus, Daria Guseva, Michał Stawarski, Malte Butzlaff, Joanna Dzwonek, Jenny Schneeberg, Katrin Böhm, Piotr Michaluk, Dmitri A. Rusakov, Alexander Dityatev, Grzegorz Wilczyński, Jakub Wlodarczyk, Evgeni Ponimaskin
Rewiring of synaptic circuitry pertinent to memory formation has been associated with morphological changes in dendritic spines and with extracellular matrix (ECM) remodeling. Here, we mechanistically link these processes by uncovering a signaling pathway involving the serotonin 5-HT7 receptor (5-HT7R), matrix metalloproteinase 9 (MMP-9), the hyaluronan receptor CD44, and the small GTPase Cdc42. We highlight a physical interaction between 5-HT7R and CD44 (identified as an MMP-9 substrate in neurons) and find that 5-HT7R stimulation increases local MMP-9 activity, triggering dendritic spine remodeling, synaptic pruning, and impairment of long-term potentiation (LTP). The underlying molecular machinery involves 5-HT7R-mediated activation of MMP-9, which leads to CD44 cleavage followed by Cdc42 activation. One important physiological consequence of this interaction includes an increase in neuronal outgrowth and elongation of dendritic spines, which might have a positive effect on complex neuronal processes (e.g., reversal learning and neuronal regeneration).

Graphical abstract

Teaser

Bijata et al. examine a signaling module involving the 5-HT7 receptor (5-HT7R), matrix metalloproteinase 9 (MMP-9), the hyaluronan receptor CD44, and the small GTPase Cdc42. Stimulation of 5-HT7R results in MMP-9 activation, which, in turn, cleaves CD44. This results in local detachment from the ECM, thus facilitating spine elongation via 5-HT7R/Cdc42 signaling.


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A Glio-Protective Role of mir-263a by Tuning Sensitivity to Glutamate

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Sherry Shiying Aw, Isaac Kok Hwee Lim, Melissa Xue Mei Tang, Stephen Michael Cohen
Glutamate is a ubiquitous neurotransmitter, mediating information flow between neurons. Defects in the regulation of glutamatergic transmission can result in glutamate toxicity, which is associated with neurodegeneration. Interestingly, glutamate receptors are expressed in glia, but little is known about their function, and the effects of their misregulation, in these non-neuronal cells. Here, we report a glio-protective role for Drosophila mir-263a mediated by its regulation of glutamate receptor levels in glia. mir-263a mutants exhibit a pronounced movement defect due to aberrant overexpression of CG5621/Grik, Nmdar1, and Nmdar2. mir-263a mutants exhibit excitotoxic death of a subset of astrocyte-like and ensheathing glia in the CNS. Glial-specific normalization of glutamate receptor levels restores cell numbers and suppresses the movement defect. Therefore, microRNA-mediated regulation of glutamate receptor levels protects glia from excitotoxicity, ensuring CNS health. Chronic low-level glutamate receptor overexpression due to mutations affecting microRNA (miRNA) regulation might contribute to glial dysfunction and CNS impairment.

Graphical abstract

Teaser

Excessive glutamatergic signaling can cause neurodegeneration. Aw et al. report that Drosophila mir-263a limits glutamate receptor levels in a subset of glia, protecting them from excitotoxicity. mir-263a mutants exhibit severe movement defects. This study reveals a mechanism by which glia protect themselves from excess glutamate signaling to maintain CNS health.


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ER Stress Inhibits Liver Fatty Acid Oxidation while Unmitigated Stress Leads to Anorexia-Induced Lipolysis and Both Liver and Kidney Steatosis

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Diane DeZwaan-McCabe, Ryan D. Sheldon, Michelle C. Gorecki, Deng-Fu Guo, Erica R. Gansemer, Randal J. Kaufman, Kamal Rahmouni, Matthew P. Gillum, Eric B. Taylor, Lynn M. Teesch, D. Thomas Rutkowski
The unfolded protein response (UPR), induced by endoplasmic reticulum (ER) stress, regulates the expression of factors that restore protein folding homeostasis. However, in the liver and kidney, ER stress also leads to lipid accumulation, accompanied at least in the liver by transcriptional suppression of metabolic genes. The mechanisms of this accumulation, including which pathways contribute to the phenotype in each organ, are unclear. We combined gene expression profiling, biochemical assays, and untargeted lipidomics to understand the basis of stress-dependent lipid accumulation, taking advantage of enhanced hepatic and renal steatosis in mice lacking the ER stress sensor ATF6α. We found that impaired fatty acid oxidation contributed to the early development of steatosis in the liver but not the kidney, while anorexia-induced lipolysis promoted late triglyceride and free fatty acid accumulation in both organs. These findings provide evidence for both direct and indirect regulation of peripheral metabolism by ER stress.

Graphical abstract

Teaser

The mechanisms by which the liver and kidney become steatotic when challenged by ER stress are not known. DeZwaan-McCabe et al. show that ER stress inhibits fatty acid oxidation in the liver and that unmitigated stress causes anorexia and promotes adipose lipolysis and further steatosis in the liver and kidney.


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Progressive Motor Neuron Pathology and the Role of Astrocytes in a Human Stem Cell Model of VCP-Related ALS

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Claire E. Hall, Zhi Yao, Minee Choi, Giulia E. Tyzack, Andrea Serio, Raphaelle Luisier, Jasmine Harley, Elisavet Preza, Charlie Arber, Sarah J. Crisp, P. Marc D. Watson, Dimitri M. Kullmann, Andrey Y. Abramov, Selina Wray, Russell Burley, Samantha H.Y. Loh, L. Miguel Martins, Molly M. Stevens, Nicholas M. Luscombe, Christopher R. Sibley, Andras Lakatos, Jernej Ule, Sonia Gandhi, Rickie Patani
Motor neurons (MNs) and astrocytes (ACs) are implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS), but their interaction and the sequence of molecular events leading to MN death remain unresolved. Here, we optimized directed differentiation of induced pluripotent stem cells (iPSCs) into highly enriched (> 85%) functional populations of spinal cord MNs and ACs. We identify significantly increased cytoplasmic TDP-43 and ER stress as primary pathogenic events in patient-specific valosin-containing protein (VCP)-mutant MNs, with secondary mitochondrial dysfunction and oxidative stress. Cumulatively, these cellular stresses result in synaptic pathology and cell death in VCP-mutant MNs. We additionally identify a cell-autonomous VCP-mutant AC survival phenotype, which is not attributable to the same molecular pathology occurring in VCP-mutant MNs. Finally, through iterative co-culture experiments, we uncover non-cell-autonomous effects of VCP-mutant ACs on both control and mutant MNs. This work elucidates molecular events and cellular interplay that could guide future therapeutic strategies in ALS.

Graphical abstract

Teaser

Hall et al. use iPSCs to examine the sequence of events by which motor neurons degenerate in a genetic form of ALS. They find that astrocytes, a type of supportive cell, also degenerate under these conditions. The ALS-causing mutation disrupts the ability of astrocytes to promote survival of motor neurons.


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Oxysterol-Binding Protein-Related Protein 1L Regulates Cholesterol Egress from the Endo-Lysosomal System

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Kexin Zhao, Neale D. Ridgway
Lipoprotein cholesterol is delivered to the limiting membrane of late endosomes/lysosomes (LELs) by Niemann-Pick C1 (NPC1). However, the mechanism of cholesterol transport from LELs to the endoplasmic reticulum (ER) is poorly characterized. We report that oxysterol-binding protein-related protein 1L (ORP1L) is necessary for this stage of cholesterol export. CRISPR-mediated knockout of ORP1L in HeLa and HEK293 cells reduced esterification of cholesterol to the level in NPC1 knockout cells, and it increased the expression of sterol-regulated genes and de novo cholesterol synthesis, indicative of a block in cholesterol transport to the ER. In the absence of this transport pathway, cholesterol-enriched LELs accumulated in the Golgi/perinuclear region. Cholesterol delivery to the ER required the sterol-, phosphatidylinositol 4-phosphate-, and vesicle-associated membrane protein-associated protein (VAP)-binding activities of ORP1L, as well as NPC1 expression. These results suggest that ORP1L-dependent membrane contacts between LELs and the ER coordinate cholesterol transfer with the retrograde movement of endo-lysosomal vesicles.

Graphical abstract

Teaser

Cholesterol is delivered to the limiting membrane of late endosomes/lysosomes (LELs) by Niemann-Pick C1 (NPC1), but how cholesterol is subsequently transported to organelles is poorly characterized. Zhao and Ridgway find that OSBP-related protein 1L (ORP1L) mediates cholesterol transfer from LELs to the endoplasmic reticulum (ER) at contacts between these organelles.


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Replication-Coupled Dilution of H4K20me2 Guides 53BP1 to Pre-replicative Chromatin

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Stefania Pellegrino, Jone Michelena, Federico Teloni, Ralph Imhof, Matthias Altmeyer
The bivalent histone modification reader 53BP1 accumulates around DNA double-strand breaks (DSBs), where it dictates repair pathway choice decisions by limiting DNA end resection. How this function is regulated locally and across the cell cycle to channel repair reactions toward non-homologous end joining (NHEJ) in G1 and promote homology-directed repair (HDR) in S/G2 is insufficiently understood. Here, we show that the ability of 53BP1 to accumulate around DSBs declines as cells progress through S phase and reveal that the inverse relationship between 53BP1 recruitment and replicated chromatin is linked to the replication-coupled dilution of 53BP1’s target mark H4K20me2. Consistently, premature maturation of post-replicative chromatin restores H4K20me2 and rescues 53BP1 accumulation on replicated chromatin. The H4K20me2-mediated chromatin association of 53BP1 thus represents an inbuilt mechanism to distinguish DSBs in pre- versus post-replicative chromatin, allowing for localized repair pathway choice decisions based on the availability of replication-generated template strands for HDR.

Graphical abstract

Teaser

Pellegrino et al. report how replication-dependent differences in chromatin inform the DNA damage response machinery about the replication status of broken genomic loci. This chromatin-embedded information affects 53BP1 binding and directs the choice of repair pathway used to fix DNA double-strand breaks.


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Mad2 Overexpression Uncovers a Critical Role for TRIP13 in Mitotic Exit

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Daniel Henry Marks, Rozario Thomas, Yvette Chin, Riddhi Shah, Christine Khoo, Robert Benezra
The mitotic checkpoint ensures proper segregation of chromosomes by delaying anaphase until all kinetochores are bound to microtubules. This inhibitory signal is composed of a complex containing Mad2, which inhibits anaphase progression. The complex can be disassembled by p31^comet and TRIP13; however, TRIP13 knockdown has been shown to cause only a mild mitotic delay. Overexpression of checkpoint genes, as well as TRIP13, is correlated with chromosomal instability (CIN) in cancer, but the initial effects of Mad2 overexpression are prolonged mitosis and decreased proliferation. Here, we show that TRIP13 overexpression significantly reduced, and TRIP13 reduction significantly exacerbated, the mitotic delay associated with Mad2 overexpression, but not that induced by microtubule depolymerization. The combination of Mad2 overexpression and TRIP13 loss reduced the ability of checkpoint complexes to disassemble and significantly inhibited the proliferation of cells in culture and tumor xenografts. These results identify an unexpected dependency on TRIP13 in cells overexpressing Mad2.

Graphical abstract

Teaser

TRIP13 is a putative mitotic checkpoint silencing protein. However, depletion of TRIP13 causes only mild mitotic exit phenotypes. Marks et al. find that TRIP13 becomes critical for mitotic exit in Mad2-overexpressing cells. Both proteins are co-overexpressed in cancer, and TRIP13 may be a therapeutic target in Mad2-overexpressing tumors.


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2-HG Inhibits Necroptosis by Stimulating DNMT1-Dependent Hypermethylation of the RIP3 Promoter

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Zhentao Yang, Bin Jiang, Yan Wang, Hengxiao Ni, Jia Zhang, Jinmei Xia, Minggang Shi, Li-Man Hung, Jingsong Ruan, Tak Wah Mak, Qinxi Li, Jiahuai Han
2-hydroxyglutarate-(2-HG)-mediated inhibition of TET2 activity influences DNA hypermethylation in cells harboring mutations of isocitrate dehydrogenases 1 and 2 (IDH1/2). Here, we show that 2-HG also regulates DNA methylation mediated by DNA methyltransferase 1 (DNMT1). DNMT1-dependent hypermethylation of the RIP3 promoter occurred in both IDH1 R132Q knockin mutant mouse embryonic fibroblast (MEFs) and 2-HG-treated wild-type (WT) MEFs. We found that 2-HG bound to DNMT1 and stimulated its association with the RIP3 promoter, inducing hypermethylation that reduces RIP3 protein and consequently impaired RIP3-dependent necroptosis. In human glioma samples, RIP3 protein levels correlated negatively with IDH1 R132H levels. Furthermore, ectopic expression of RIP3 in transformed IDH1-mutated MEFs inhibited the growth of tumors derived from these cells following transplantation into nude mice. Thus, our research sheds light on a mechanism of 2-HG-induced DNA hypermethylation and suggests that impaired necroptosis contributes to the tumorigenesis driven by IDH1/2 mutations.

Graphical abstract

Teaser

Yang et al. report that oncometabolite 2-HG produced by tumor-associated IDH1 mutation physically binds to DNMT1 and stimulates its association with the RIP3 promoter, inducing hypermethylation that reduces RIP3 protein and consequently impaired RIP3-dependent necroptosis. Loss of RIP3-mediated necroptosis contributes to tumorigenesis driven by 2-HG.


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Cancer-Associated IDH1 Promotes Growth and Resistance to Targeted Therapies in the Absence of Mutation

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Andrea E. Calvert, Alexandra Chalastanis, Yongfei Wu, Lisa A. Hurley, Fotini M. Kouri, Yingtao Bi, Maureen Kachman, Jasmine L. May, Elizabeth Bartom, Youjia Hua, Rama K. Mishra, Gary E. Schiltz, Oleksii Dubrovskyi, Andrew P. Mazar, Marcus E. Peter, Hongwu Zheng, C. David James, Charles F. Burant, Navdeep S. Chandel, Ramana V. Davuluri, Craig Horbinski, Alexander H. Stegh
Oncogenic mutations in two isocitrate dehydrogenase (IDH)-encoding genes (IDH1 and IDH2) have been identified in acute myelogenous leukemia, low-grade glioma, and secondary glioblastoma (GBM). Our in silico and wet-bench analyses indicate that non-mutated IDH1 mRNA and protein are commonly overexpressed in primary GBMs. We show that genetic and pharmacologic inactivation of IDH1 decreases GBM cell growth, promotes a more differentiated tumor cell state, increases apoptosis in response to targeted therapies, and prolongs the survival of animal subjects bearing patient-derived xenografts (PDXs). On a molecular level, diminished IDH1 activity results in reduced α-ketoglutarate (αKG) and NADPH production, paralleled by deficient carbon flux from glucose or acetate into lipids, exhaustion of reduced glutathione, increased levels of reactive oxygen species (ROS), and enhanced histone methylation and differentiation marker expression. These findings suggest that IDH1 upregulation represents a common metabolic adaptation by GBMs to support macromolecular synthesis, aggressive growth, and therapy resistance.

Graphical abstract

Teaser

Calvert et al. demonstrate that wild-type IDH1 is overexpressed in glioblastoma and that genetic or pharmacological suppression of IDH1 activity reduces tumor cell growth through effect on lipid production, redox homeostasis, and the regulation of cellular differentiation.


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A TLR3-Specific Adjuvant Relieves Innate Resistance to PD-L1 Blockade without Cytokine Toxicity in Tumor Vaccine Immunotherapy

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Yohei Takeda, Keisuke Kataoka, Junya Yamagishi, Seishi Ogawa, Tsukasa Seya, Misako Matsumoto
Cancer patients having anti-programmed cell death-1 (PD-1)/PD ligand 1 (L1)-unresponsive tumors may benefit from advanced immunotherapy. Double-stranded RNA triggers dendritic cell (DC) maturation to cross-prime antigen-specific cytotoxic T lymphocytes (CTLs) via Toll-like receptor 3 (TLR3). The TLR3-specific RNA agonist, ARNAX, can induce anti-tumor CTLs without systemic cytokine/interferon (IFN) production. Here, we have developed a safe vaccine adjuvant for cancer that effectively implements anti-PD-L1 therapy. Co-administration of ARNAX with a tumor-associated antigen facilitated tumor regression in mouse models, and in combination with anti-PD-L1 antibody, activated tumor-specific CTLs in lymphoid tissues, enhanced CTL infiltration, and overcame anti-PD-1 resistance without cytokinemia. The TLR3-TICAM-1-interferon regulatory factor (IRF)3-IFN-β axis in DCs exclusively participated in CD8⁺ T cell cross-priming. ARNAX therapy established Th1 immunity in the tumor microenvironment, upregulating genes involved in DC/T cell/natural killer (NK) cell recruitment and functionality. Human ex vivo studies disclosed that ARNAX+antigen induced antigen-specific CTL priming and proliferation in peripheral blood mononuclear cells (PBMCs), supporting the feasibility of ARNAX for potentiating anti-PD-1/PD-L1 therapy in human vaccine immunotherapy.

Graphical abstract

Teaser

PD-1 blockade benefits a small proportion of cancer patients with pre-existing anti-tumor CTLs. Takeda et al. show that the TLR3-specific ligand, ARNAX, and tumor-associated antigens (TAAs) induce anti-tumor CTLs, establish Th1-type anti-tumor immunity, and lead to tumor regression without inflammation. Combination therapy using ARNAX/TAA and anti-PD-L1 Ab overcomes PD-1 blockade-unresponsiveness.


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Genome-wide Analysis of STAT3-Mediated Transcription during Early Human Th17 Cell Differentiation

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Subhash K. Tripathi, Zhi Chen, Antti Larjo, Kartiek Kanduri, Kari Nousiainen, Tarmo Äijo, Isis Ricaño-Ponce, Barbara Hrdlickova, Soile Tuomela, Essi Laajala, Verna Salo, Vinod Kumar, Cisca Wijmenga, Harri Lähdesmäki, Riitta Lahesmaa
The development of therapeutic strategies to combat immune-associated diseases requires the molecular mechanisms of human Th17 cell differentiation to be fully identified and understood. To investigate transcriptional control of Th17 cell differentiation, we used primary human CD4⁺ T cells in small interfering RNA (siRNA)-mediated gene silencing and chromatin immunoprecipitation followed by massive parallel sequencing (ChIP-seq) to identify both the early direct and indirect targets of STAT3. The integrated dataset presented in this study confirms that STAT3 is critical for transcriptional regulation of early human Th17 cell differentiation. Additionally, we found that a number of SNPs from loci associated with immune-mediated disorders were located at sites where STAT3 binds to induce Th17 cell specification. Importantly, introduction of such SNPs alters STAT3 binding in DNA affinity precipitation assays. Overall, our study provides important insights for modulating Th17-mediated pathogenic immune responses in humans.

Graphical abstract

Teaser

Tripathi et al. show that STAT3 is critical for transcriptional regulation of early human Th17 cell differentiation. A number of SNPs from loci associated with immune-mediated disorders occur at STAT3-binding sites. Introduction of such SNPs alters STAT3 binding in DNA affinity precipitation assays.


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Specification and Diversification of Pericytes and Smooth Muscle Cells from Mesenchymoangioblasts

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Akhilesh Kumar, Saritha Sandra D’Souza, Oleg V. Moskvin, Huishi Toh, Bowen Wang, Jue Zhang, Scott Swanson, Lian-Wang Guo, James A. Thomson, Igor I. Slukvin
Elucidating the pathways that lead to vasculogenic cells, and being able to identify their progenitors and lineage-restricted cells, is critical to the establishment of human pluripotent stem cell (hPSC) models for vascular diseases and development of vascular therapies. Here, we find that mesoderm-derived pericytes (PCs) and smooth muscle cells (SMCs) originate from a clonal mesenchymal progenitor mesenchymoangioblast (MB). In clonogenic cultures, MBs differentiate into primitive PDGFRβ⁺CD271⁺CD73⁻ mesenchymal progenitors, which give rise to proliferative PCs, SMCs, and mesenchymal stem/stromal cells. MB-derived PCs can be further specified to CD274⁺ capillary and DLK1⁺ arteriolar PCs with a proinflammatory and contractile phenotype, respectively. SMC maturation was induced using a MEK inhibitor. Establishing the vasculogenic lineage tree, along with identification of stage- and lineage-specific markers, provides a platform for interrogating the molecular mechanisms that regulate vasculogenic cell specification and diversification and manufacturing well-defined mural cell populations for vascular engineering and cellular therapies from hPSCs.

Graphical abstract

Teaser

Kumar et al. find that mesodermal pericytes and smooth muscle cells in human pluripotent stem cell cultures originate from a common endothelial and mesenchymal cell precursor, the mesenchymoangioblast. They show how different lineages of mural cells are specified from mesenchymoangioblasts and define stage- and lineage-specific markers for vasculogenic cells.


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Structural Basis of the Human Endoglin-BMP9 Interaction: Insights into BMP Signaling and HHT1

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Takako Saito, Marcel Bokhove, Romina Croci, Sara Zamora-Caballero, Ling Han, Michelle Letarte, Daniele de Sanctis, Luca Jovine
Endoglin (ENG)/CD105 is an essential endothelial cell co-receptor of the transforming growth factor β (TGF-β) superfamily, mutated in hereditary hemorrhagic telangiectasia type 1 (HHT1) and involved in tumor angiogenesis and preeclampsia. Here, we present crystal structures of the ectodomain of human ENG and its complex with the ligand bone morphogenetic protein 9 (BMP9). BMP9 interacts with a hydrophobic surface of the N-terminal orphan domain of ENG, which adopts a new duplicated fold generated by circular permutation. The interface involves residues mutated in HHT1 and overlaps with the epitope of tumor-suppressing anti-ENG monoclonal TRC105. The structure of the C-terminal zona pellucida module suggests how two copies of ENG embrace homodimeric BMP9, whose binding is compatible with ligand recognition by type I but not type II receptors. These findings shed light on the molecular basis of the BMP signaling cascade, with implications for future therapeutic interventions in this fundamental pathway.

Graphical abstract

Teaser

Endoglin (ENG)/CD105, a key player in angiogenesis and vascular homeostasis, is mutated in the genetic disorder HHT1 and implicated in tumor angiogenesis and preeclampsia. Saito et al. determine structures of human ENG alone and in complex with the physiological ligand BMP9, shedding light onto the molecular basis of BMP signaling.


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Sequential Steps of CRAC Channel Activation

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Raz Palty, Zhu Fu, Ehud Y. Isacoff
Interaction between the endoplasmic reticulum protein STIM1 and the plasma membrane channel ORAI1 generates calcium signals that are central for diverse cellular functions. How STIM1 binds and activates ORAI1 remains poorly understood. Using electrophysiological, optical, and biochemical techniques, we examined the effects of mutations in the STIM1-ORAI1 activating region (SOAR) of STIM1. We find that SOAR mutants that are deficient in binding to resting ORAI1 channels are able to bind to and boost activation of partially activated ORAI1 channels. We further show that the STIM1 binding regions on ORAI1 undergo structural rearrangement during channel activation. The results suggest that activation of ORAI1 by SOAR occurs in multiple steps. In the first step, SOAR binds to ORAI1, partially activates the channel, and induces a rearrangement in the SOAR-binding site of ORAI1. That rearrangement of ORAI1 then permits sequential steps of SOAR binding, via distinct molecular interactions, to fully activate the channel.

Graphical abstract

Teaser

How the interaction between STIM1 and the ORAI1 CRAC channel activates ORAI1 is poorly understood. Palty et al. identify mutations in STIM1 that disrupt partial activation but support the transition from partial to full activation. The study reveals the existence of sequential modes of STIM1-ORAI1 interaction.


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Effect of Human Genetic Variability on Gene Expression in Dorsal Root Ganglia and Association with Pain Phenotypes

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Marc Parisien, Samar Khoury, Anne-Julie Chabot-Doré, Susana G. Sotocinal, Gary D. Slade, Shad B. Smith, Roger B. Fillingim, Richard Ohrbach, Joel D. Greenspan, William Maixner, Jeffrey S. Mogil, Inna Belfer, Luda Diatchenko
Dorsal root ganglia (DRG) relay sensory information to the brain, giving rise to the perception of pain, disorders of which are prevalent and burdensome. Here, we mapped expression quantitative trait loci (eQTLs) in a collection of human DRGs. DRG eQTLs were enriched within untranslated regions of coding genes of low abundance, with some overlapping with other brain regions and blood cell cis-eQTLs. We confirm functionality of identified eQTLs through their significant enrichment within open chromatin and highly deleterious SNPs, particularly at the exon level, suggesting substantial contribution of eQTLs to alternative splicing regulation. We illustrate pain-related genetic association results explained by DRG eQTLs, with the strongest evidence for contribution of the human leukocyte antigen (HLA) locus, confirmed using a mouse inflammatory pain model. Finally, we show that DRG eQTLs are found among hits in numerous genome-wide association studies, suggesting that this dataset will help address pain components of non-pain disorders.

Graphical abstract

Teaser

Parisien et al. present a database of expression quantitative trait loci in human dorsal root ganglia. The dataset represents a tool for interpreting human GWAS with sensory components. Its analysis demonstrates contributions of the HLA locus to pain phenotypes.


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Quantitative Cell Cycle Analysis Based on an Endogenous All-in-One Reporter for Cell Tracking and Classification

Publication date: 30 May 2017
Source:Cell Reports, Volume 19, Issue 9
Author(s): Thomas Zerjatke, Igor A. Gak, Dilyana Kirova, Markus Fuhrmann, Katrin Daniel, Magdalena Gonciarz, Doris Müller, Ingmar Glauche, Jörg Mansfeld
Cell cycle kinetics are crucial to cell fate decisions. Although live imaging has provided extensive insights into this relationship at the single-cell level, the limited number of fluorescent markers that can be used in a single experiment has hindered efforts to link the dynamics of individual proteins responsible for decision making directly to cell cycle progression. Here, we present fluorescently tagged endogenous proliferating cell nuclear antigen (PCNA) as an all-in-one cell cycle reporter that allows simultaneous analysis of cell cycle progression, including the transition into quiescence, and the dynamics of individual fate determinants. We also provide an image analysis pipeline for automated segmentation, tracking, and classification of all cell cycle phases. Combining the all-in-one reporter with labeled endogenous cyclin D1 and p21 as prime examples of cell-cycle-regulated fate determinants, we show how cell cycle and quantitative protein dynamics can be simultaneously extracted to gain insights into G1 phase regulation and responses to perturbations.

Graphical abstract

Teaser

Zerjatke et al. present endogenously tagged PCNA as an all-in-one cell cycle reporter for living cells to classify all cell cycle phases and quiescence using a single fluorescent channel. Visualizing endogenous cyclin D1 in living cells, they show that cyclin D1 maintains G1 phase and prevents the transition into quiescence.


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Smoking not only burns lungs, it affects your ENT health too - Times of India

Times of India

Smoking not only burns lungs, it affects your ENT health too Times of India "Tobacco, apart from being a leading causative factor for cancer, also causes multiple ENT related diseases. The lining of the nose and sinuses is similar to the lining in the lungs. There are cilia, or tiny hair-like structures, that clean the nose ...

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Development of a 12-item short version of the HIV stigma scale

Valid and reliable instruments for the measurement of enacted, anticipated and internalised stigma in people living with HIV are crucial for mapping trends in the prevalence of HIV-related stigma and tracking ...

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“Fibromyalgia and quality of life: mapping the revised fibromyalgia impact questionnaire to the preference-based instruments”

The revised version of the Fibromyalgia Impact Questionnaire (FIQR) is one of the most widely used specific questionnaires in FM studies. However, this questionnaire does not allow calculation of QALYs as it i...

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Cross-cultural measurement invariance in the satisfaction with food-related life scale in older adults from two developing countries

Nutrition is one of the major determinants of successful aging. The Satisfaction with Food-related Life (SWFL) scale measures a person’s overall assessment regarding their food and eating habits. The SWFL scal...

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Targeting of super-enhancers and mutant BRAF can suppress growth of BRAF-mutant colon cancer cells via repression of MAPK signaling pathway

Bromodomain and extra-terminal (BET) inhibitors suppress super-enhancers and show cytotoxicity against multiple types of tumors. However, early clinical trials with BET inhibitors showed severe hematopoietic toxicities, highlighting the need for sensitive tumors and rational combination strategies to enhance their therapeutic potential. Here, we identified colon cancer-specific super-enhancers that were associated with multiple oncogenic pathways, including the mitogen-activated protein kinase (MAPK) signaling pathway.

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BZML, a novel colchicine binding site inhibitor, overcomes multidrug resistance in A549/Taxol cells by inhibiting P-gp function and inducing mitotic catastrophe

Multidrug resistance (MDR) interferes with the efficiency of chemotherapy. Therefore, developing novel anti-cancer agents that can overcome MDR is necessary. Here, we screened a series of colchicine binding site inhibitors (CBSIs) and found that 5-(3, 4, 5-trimethoxybenzoyl)-4-methyl-2-(p-tolyl) imidazol (BZML) displayed potent cytotoxic activity against both A549 and A549/Taxol cells. We further explored the underlying mechanisms and found that BZML caused mitosis phase arrest by inhibiting tubulin polymerization in A549 and A549/Taxol cells.

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Response to “Circular RNA profile identifies circPVT1 as a proliferative factor and prognostic marker in gastric cancer,” Cancer Lett. 2017 Mar 1; 388(2017): 208-219

We much appreciated for the comment on our manuscript[1]. However, there are some misunderstanding in this comment. Firstly, the authors concluded that circPVT1 played a cancer suppressor role in vivo (from the clinical correlation), while was proved to act an oncogene in vitro (from the functional assays). However, the clinical correlation (biomarker) may have no functional implication. We were also very curious about the contradiction between clinical implication and cellular function of circPVT1 in GC.

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A combinatorial strategy using YAP and pan-RAF inhibitors for treating KRAS-mutant pancreatic cancer

KRAS mutation is the most common genetic event in pancreatic cancer. Whereas KRAS itself has proven difficult to inhibit, agents that target key downstream signals of KRAS, such as RAF, are possibly effective for pancreatic cancer treatment. Because selective BRAF inhibitors paradoxically induce downstream signaling activation, a pan-RAF inhibitor, LY3009120 is a better alternate for KRAS-mutant tumor treatment. Here we explored a new combinational strategy using a YAP inhibitor and LY3009120 in pancreatic cancer treatment.

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Tamoxifen acceptance and adherence among patients with ductal carcinoma in situ (DCIS) treated in a multidisciplinary setting.

Tamoxifen and other endocrine agents have proven benefits for women with ductal carcinoma in situ (DCIS) but low patient acceptance is widely reported. We examined factors associated with tamoxifen acceptance and adherence among DCIS patients who received a recommendation for therapy in a multidisciplinary setting. <p>Using our institutional database, we identified women diagnosed with DCIS, 1998-2009 who were offered tamoxifen. We recorded data on demographics, tumor and therapy variables, tamoxifen acceptance, and adherence to therapy for > 4 years. Univariable and multivariable analyses were conducted using logistic regression, to identify factors specific to each group that were related to acceptance and adherence.</p> <p>555 eligible women identified, of whom 369 were offered tamoxifen; 298 (81%) accepted, among whom 214 (72%) were adherent, 59/298 (20%) were nonadherent, and for 25 (8%) adherence was undetermined. After stepwise elimination in adjusted logistic regression models, acceptance of breast radiotherapy was associated with acceptance of tamoxifen (odds ratio [OR] 2.22, 95% Confidence Interval [CI] 1.26-3.90, p<0.01), as was a medical oncology consultation (OR 1.76, 95% CI 0.99-3.15, p=0.05). Insured patients were more likely to adhere to tamoxifen, (OR 6.03, 95% CI 2.60-13.98, p<0.01). The majority of nonadherent women (n=38/56, 68%) discontinued the drug during the first year of treatment with 48 (86%) citing adverse effect(s) as the reason.</p> <p>In a multidisciplinary, tertiary care setting, we observed relatively high rates of acceptance and adherence of tamoxifen. Acceptance of tamoxifen and radiotherapy were associated, and adherence was influenced by insurance status.

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Development of a cancer risk prediction tool for use in the UK Primary Care and community settings.

Several multivariable risk prediction models have been developed to asses an individual's risk of developing specific cancers. Such models can be used in a variety of settings for prevention, screening and guiding investigations and treatments. Models aimed at predicting future disease risk that contains lifestyle factors may be of particular use for targeting health promotion activities at an individual level. This type of cancer risk prediction is not yet available in the UK. We have adopted the approach used by the well-established U.S. derived "YourCancerRisk" model for use in the UK population which allow users to quantify their individual risk of developing individual cancers relative to the population average risk. The UK version of YourCancerRisk" computes 10 year cancer risk estimates for 11 cancers utilising UK figures for prevalence of risk factors and cancer incidence. Since the prevalence of risk factors and the incidence rates for cancer are different between the US and the UK population, this UK model provides more accurate estimates of risks for a UK population.  Using an example of breast cancer and data from UK Biobank cohort we demonstrate that the individual risk factor estimates are similar for the US and UK populations. Assessment of the performance and validation of the multivariate model predictions based on a binary score confirm the model's applicability. The model can be used to estimate absolute and relative cancer risk for use in Primary Care and community settings and is being used in the community to guide lifestyle change.

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The impact of a multifaceted intervention including sepsis electronic alert system and sepsis response team on the outcomes of patients with sepsis and septic shock

Compliance with the clinical practice guidelines of sepsis management has been low. The objective of our study was to describe the results of implementing a multifaceted intervention including an electronic al...

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Kr-POK (ZBTB7c) regulates cancer cell proliferation through glutamine metabolism

Publication date: Available online 30 May 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Man-Wook Hur, Jae-Hyeon Yoon, Min-Young Kim, Hyeonseok Ko, Bu-Nam Jeon
Kr-POK (ZBTB7c) is a kidney cancer-related POK transcription factor that not only represses transcription of CDKN1A but also increases expression of FASN. However, precisely how Kr-POK affects cell metabolism by controlling gene expression in response to an energy source in rapidly proliferating cells remains unknown. In this study, we characterized the molecular and functional features of Kr-POK in the context of tumor growth and glutamine metabolism. We found that cells expressing Kr-POK shRNA exhibited more severe cell death than control cells in glucose-deprived medium, and that knockdown of Kr-POK decreased glutamine uptake. Glutamine is critical for tumor cell proliferation. Glutaminase (GLS1), which is activated by p-STAT1, catalyzes the initial reaction in the pathway of glutaminolysis. Kr-POK interacts with PIAS1 to disrupt the interaction between PIAS1 and p-STAT1, and free p-STAT1 can activate GLS1 transcription through an interaction with p300. Kr-POK can be also sumoylated by PIAS1, facilitating Kr-POK degradation by the ubiquitin-mediated proteasomal pathway. Finally, we showed that repression of Kr-POK inhibited tumor growth in vivo in a xenograft model by repressing GLS1 expression. Taken together, our data reveal that Kr-POK activates GLS1 transcription and increases glutamine uptake to support rapid cancer cell proliferation.



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Acetylation of MKL1 by PCAF regulates pro-inflammatory transcription

Publication date: Available online 30 May 2017
Source:Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms
Author(s): Liming Yu, Zilong Li, Mingming Fang, Yong Xu
Inflammation is considered a fundamental host defense mechanism and, when aberrantly activated, contributes to a host of human diseases. Previously we have reported that the transcriptional regulator megakaryocytic leukemia 1 (MKL1) plays a role programming cellular inflammatory response by modulating NF-κB activity. Here we report that MKL1 was acetylated in vivo and pro-inflammatory stimuli (TNF-α and LPS) augmented MKL1 acetylation accompanying increased MKL1 binding to NF-κB target promoters. Further analysis revealed that the lysine acetyltransferase PCAF mediated MKL1 acetylation: TNF-α and LPS promoted the interaction between MKL1 and PCAF while depletion of PCAF abrogated the induction of MKL1 acetylation by TNF-α and LPS. Acetylation of MKL1 was necessary for MKL1 to activate the transcription of pro-inflammatory genes because mutation of four conserved lysine residues in MKL1 attenuated its capacity as a trans-activator of NF-κB target genes. Mechanistically, MKL1 acetylation served to promote MKL1 nuclear enrichment, to enhance the MKL1-NF-κB interaction, and to stabilize the binding of MKL1 on target promoters. In conclusion, our data unveil an important pathway that contributes to the transcriptional regulation of inflammatory response.



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Woman credits faith and exercise with helping her beat cancer - Gaffney Ledger (subscription)

Woman credits faith and exercise with helping her beat cancer Gaffney Ledger (subscription) Jeanne Hames has beaten death twice after the nonsmoker was diagnosed with tongue and lung cancer over the past five years. She credits her faith and exercise with helping her in a successful battle against the disease. and more »

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Un reggiseno speciale per riconoscere il tumore al seno - Emilia-Romagna Mamma (Comunicati Stampa) (Blog)

Emilia-Romagna Mamma (Comunicati Stampa) (Blog)

Un reggiseno speciale per riconoscere il tumore al seno Emilia-Romagna Mamma (Comunicati Stampa) (Blog) Con la sua Higia Tecnhologies, Julian vuole aiutare le donne a prevenire il cancro al seno e lo fa, appunto, con un reggiseno – denominato “Eva” – in grado di rilevare i sintomi di questo tipo di tumore. ... Il docetaxel, che può essere utilizzato da ... An 18-year-old boy has invented a bra that detects breast cancerThe indy100 Teenager invents a bra that could detect BREAST CANCER after watching his mum's battle with diseaseThe Sun 18-year-old Mexican student designs bra that can detect breast cancerThe Independent all 47 news articles »

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Nicotine is more addictive and deadlier than cocaine - Daily News & Analysis

Daily News & Analysis

Nicotine is more addictive and deadlier than cocaine Daily News & Analysis Chewing tobacco in forms such as paan, sopari, etc causes cancers of the tongue, cheek, various parts of the mouth and the throat. These oral cancers make up almost 25 per cent of all the male cancers in India. Lung cancers make up an additional 8 per ...

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In vitro quality evaluation of leading brands of ciprofloxacin tablets available in Bangladesh

Ciprofloxacin is a broad-spectrum antibiotic that acts against a number of bacterial infections. The study was carried out to examine the in vitro quality control tests for ten leading brands of ciprofloxacin ...

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Molecular dynamics simulations reveal the conformational dynamics of Arabidopsis thaliana BRI1 and BAK1 receptor-like kinases [Protein Structure and Folding]

The structural motifs responsible for activation and regulation of eukaryotic protein kinases in animals have been studied extensively in recent years, and a coherent picture of their activation mechanisms has begun to emerge. On the other hand, non-animal eukaryotic protein kinases are not as well understood from a structural perspective, representing a large knowledge gap. To this end, we investigated the conformational dynamics of two key Arabidopsis thaliana receptor-like kinases, brassi- nosteroid insensitive 1 (BRI1) and BRI1-associated kinase 1 (BAK1), through extensive molecular dynamics (MD) simulations of their fully phosphorylated kinase domains. MD simulations calculate the motion of each atom in a protein based on classical approximations of interatomic forces, giving researchers insight into protein function at unparalleled spatial and temporal resolutions. We found that in an otherwise ″active″ BAK1, the αC helix is highly disordered, a hallmark of deactivation, while the BRI1 αC helix is moderately disordered and displays swinging behavior similar to numerous animal kinases. An analysis of all known sequences in the A. thaliana kinome found that αC helix disorder may be a common feature of plant kinases.

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The autism-linked UBE3A T485A mutant E3 ubiquitin ligase activates the Wnt/{beta}-catenin pathway by inhibiting the proteasome [Genomics and Proteomics]

UBE3A is a HECT domain E3 ubiquitin ligase whose dysfunction is linked to autism, Angelman syndrome, and cancer. Recently, we characterized a de novo autism-linked UBE3A mutant (UBE3AT485A) that disrupts phosphorylation control of UBE3A activity. Through quantitative proteomics and reporter assays, we found that the UBE3AT485A protein ubiquitinates multiple proteasome subunits, reduces proteasome subunit abundance and activity, stabilizes nuclear β-catenin, and stimulates canonical Wnt signaling more effectively than wild-type UBE3A. We also found that UBE3AT485A activates Wnt signaling to a greater extent in cells with low levels of ongoing Wnt signaling, suggesting that cells with low basal Wnt activity are particularly vulnerable to UBE3AT485A mutation. Ligase-dead UBE3A did not stimulate Wnt pathway activation. Overexpression of several proteasome subunits reversed the effect of UBE3AT485A on Wnt signaling. We also observed that subunits that interact with UBE3A and affect Wnt signaling are located along one side of the 19S regulatory particle, indicating a previously unrecognized spatial organization to the proteasome. Altogether, our findings indicate that UBE3A regulates Wnt signaling in a cell context-dependent manner and that an autism-linked mutation exacerbates these signaling effects. Our study has broad implications for human disorders associated with UBE3A gain or loss-of-function, and suggest that dysfunctional UBE3A might affect additional proteins and pathways that are sensitive to proteasome activity.

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Hepatitis C virus induces a pre-diabetic state by directly impairing hepatic glucose metabolism in mice [Metabolism]

Virus-related type-2 diabetes is commonly observed in individuals infected with the hepatitis C virus (HCV). However, the underlying molecular mechanisms remain unknown. Our aims were to unravel these mechanisms using FL-N/35 transgenic mice expressing the full HCV-ORF. We observed that these mice displayed glucose intolerance and insulin resistance. We also found that Glut-2 membrane expression was reduced in FL-N/35 mice and that hepatocyte glucose uptake was perturbed, partly accounting for the HCV-induced glucose intolerance in these mice. Early steps of the hepatic insulin signaling pathway, from IRS2 to PDK1 phosphorylation, were constitutively impaired in FL-N/35 primary hepatocytes, via deregulation of TNFα/SOCS3. Higher hepatic glucose production was observed in the HCV mice, despite higher fasting insulinemia, concomitantly with decreased expression of hepatic gluconeogenic genes. Akt kinase activity was higher in HCV mice than in WT mice, but Akt-dependent phosphorylation of the forkhead transcription factor FoxO1 at serine 256, which triggers its nuclear exclusion, was lower in HCV mouse livers. These findings indicate an uncoupling of the canonical Akt/FoxO1 pathway in HCV proteins-expressing hepatocytes. Thus, the expression of HCV proteins in the liver is sufficient to induce in- sulin resistance by impairing insulin signaling and glucose uptake. In conclusion, we observed a complete set of events leading to a pre-diabetic state in HCV-transgenic mice, providing a valuable mechanistic explanation for HCV-induced diabetes in humans.

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Uridine monophosphate synthetase enables eukaryotic de novo NAD+ biosynthesis from quinolinic acid [Bioenergetics]

NAD+ biosynthesis is an attractive and promising therapeutic target for influencing healthspan and obesity-related phenotypes as well as tumor growth. Full and effective use of this target for therapeutic benefit requires a complete understanding of NAD+ biosynthetic pathways. Here we report a previously unrecognized role for a conserved phosphoribosyltransferase in NAD+ biosynthesis. Because a required quinolinic acid phosphoribosyltransferase (QPRTase) is not encoded in its genome, Caenorhabditis elegans are reported to lack a de novo NAD+ biosynthetic pathway. However, all the genes of the kynurenine pathway required for quinolinic acid (QA) production from tryptophan are present. Thus, we investigated the presence of de novo NAD+ biosynthesis in this organism. By combining isotope-tracing and genetic experiments, we have demonstrated the presence of an intact de novo biosynthesis pathway for NAD+ from tryptophan via QA, highlighting the functional conservation of this important biosynthetic activity. Supplementation with kynurenine pathway intermediates also boosted NAD+ levels and partially reversed NAD+-dependent phenotypes caused by mutation of pnc-1, which encodes a nicotinamidase required for NAD+ salvage biosynthesis, demonstrating contribution of de novo synthesis to NAD+ homeostasis. By investigating candidate phosphoribosyltransferase genes in the genome, we determined that the conserved uridine monophosphate phosophoribosyltransferase (UMPS), which acts in pyrimidine biosynthesis, is required for NAD+ biosynthesis in place of the missing QPRTase. We suggest that similar underground metabolic activity of UMPS may function in other organisms. This mechanism for NAD+ biosynthesis creates novel possibilities for manipulating NAD+ biosynthetic pathways, which is key for the future of therapeutics.

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Crystal structure of the thioesterification conformation of Bacillus subtilis o-succinylbenzoyl-CoA synthetase reveals a distinct substrate binding mode [Protein Structure and Folding]

o-Succinylbenzoyl-CoA (OSB-CoA) synthetase (MenE) is an essential enzyme in bacterial vitamin K biosynthesis and an important target in the development of new antibiotics. It is a member of the adenylating enzymes (ANL) family, which reconfigure their active site in two different active conformations, one for the adenylation half-reaction and the other for a thioesterification half-reaction, in a domain-alternation catalytic mechanism. Although several aspects of the adenylating mechanism in MenE have recently been uncovered, its thioesterification conformation remains elusive. Here, using a catalytically competent Bacillus subtilis mutant protein complexed with an OSB-CoA analog, we determined MenE high-resolution structures to 1.76 and 1.90 Å resolution in a thioester-forming conformation. By comparison with the adenylation conformation, we found that MenE C-domain rotates around the Ser384 hinge by 139.5° during domain-alternation catalysis. The structures also revealed a thioesterfication active site specifically conserved among MenE orthologues and a substrate-binding mode distinct from those of many other acyl/aryl-CoA synthetases. Of note, using site-directed mutagenesis, we identified several residues that specifically contribute to the thioesterification half-reaction without affecting the adenylation half-reaction. Moreover, we observed a substantial movement of the activated succinyl group in the thioesterification half- reaction. These findings provide new insights into the domain-alternation catalysis of a bacterial enzyme essential for vitamin K biosynthesis and of its adenylating homologues in the ANL enzyme family.

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The higher plant plastid NAD(P)H dehydrogenase-like complex (NDH) is a high efficiency proton pump that increases ATP production by cyclic electron flow [Bioenergetics]

Cyclic electron flow around photosystem I (CEF) is critical for balancing the photosynthetic energy budget of the chloroplast, by generating ATP without net production of NADPH. We demonstrate that the chloroplast NADPH dehydrogenase complex (NDH), a homolog to respiratory Complex I, pumps approximately two protons from the chloroplast stroma to the lumen per electron transferred from ferredoxin to plastoquinone, effectively increasing the efficiency of ATP production via CEF by two-fold compared to CEF pathways involving non-proton-pumping plastoquinone reductases. By virtue of this proton-pumping stoichiometry, we hypothesise that NDH not only efficiently contributes to ATP production, but operates near thermodynamic reversibility, with potentially important consequences for remediating mismatches in the thylakoid energy budget.

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The UbiK protein is an accessory factor necessary for bacterial ubiquinone (UQ) biosynthesis and forms a complex with the UQ biogenesis factor UbiJ [Bioenergetics]

Ubiquinone (UQ), also referred to as coenzyme Q, is a widespread lipophilic molecule in both prokaryotes and eukaryotes in which it primarily acts as an electron carrier. Eleven proteins are known to participate in UQ biosynthesis in Escherichia coli, and we recently demonstrated that UQ biosynthesis requires additional, nonenzymatic factors, some of which are still unknown. Here, we report on the identification of a bacterial gene, yqiC, which is required for efficient UQ biosynthesis, and which we have renamed ubiK. Using several methods, we demonstrated that the UbiK protein forms a complex with the C-terminal part of UbiJ, another UQ biogenesis factor we previously identified. We found that both proteins are likely to contribute to global UQ biosynthesis rather than to a specific biosynthetic step, since both ubiK and ubiJ mutants accumulated octaprenylphenol, an early intermediate of the UQ biosynthetic pathway. Interestingly, we found that both proteins are dispensable for UQ biosynthesis under anaerobiosis, even though they were expressed in the absence of oxygen. We also provide evidence that the UbiK-UbiJ complex interacts with palmitoleic acid, a major lipid in E. coli. Last, in Salmonella enterica, ubiK was required for proliferation in macrophages and virulence in mice. We conclude that although the role of the UbiK-UbiJ complex remains unknown, our results support the hypothesis that UbiK is an accessory factor of Ubi enzymes and facilitates UQ biosynthesis by acting as an assembly factor, a targeting factor, or both.

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The p90 ribosomal S6 kinase-UBR5 pathway controls toll-like receptor signaling via miRNA-induced translational inhibition of TNF receptor-associated factor 3 [Cell Biology]

MicroRNAs (miRNAs) are small, noncoding RNAs that post-transcriptionally regulate gene expression. For example, miRNAs repress gene expression by recruiting the miRNA−induced silencing complex (miRISC), a ribonucleoprotein complex that contains miRNA−engaged Argonaute (Ago) and the scaffold protein GW182. Recently, ubiquitin protein ligase E3 component N−recognin 5 (UBR5) has been identified as a component of miRISC. UBR5 directly interacts with GW182 proteins and participates in miRNA silencing by recruiting downstream effectors, such as the translation regulator DEAD−box helicase 6 (DDX6) and transducer of ERBB2.1/2 (Tob1/2), to the Ago−GW182 complex. However, the regulation of miRISC-associated UBR5 remain largely elusive. In the present study, we show that UBR5 down−regulates the levels of TNF receptor−associated factor 3 (TRAF3), a key component of toll-like receptor signaling, via the miRNA pathway. We further demonstrate that p90 ribosomal S6 kinase (p90RSK) is an upstream regulator of UBR5. p90RSK phosphorylates UBR5 at Thr637, Ser1227, and Ser2483, and the phosphorylation is required for the translational repression of TRAF3 mRNA. Phosphorylated UBR5 co−localized with GW182 and Ago2 in cytoplasmic speckles, which implicated that miRISC is affected by phospho−UBR5. Collectively, these results indicate that the p90RSK−UBR5 pathway stimulates miRNA−mediated translational repression of TRAF3. Our work adds another layer to the regulation of miRISC.

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Cryptococcus neoformans ADS lyase in an enzyme essential for virulence whose crystal structure reveals features exploitable in antifungal drug design [Metabolism]

There is significant clinical need for new antifungal agents to manage infections with pathogenic species such as Cryptococcus neoformans. Because the purine biosynthesis pathway is essential for many metabolic processes, such as synthesis of DNA and RNA and energy generation, it may represent a potential target for developing new antifungals. Within this pathway, the bifunctional enzyme adenylosuccinate (ADS) lyase plays a role in the formation of the key intermediates inosine monophosphate and AMP involved in the synthesis of ATP and GTP, prompting us to investigate ADS lyase in C. neoformans. Here, we report that ADE13 encodes ADS lyase in C. neoformans. We found that an ade13Δ mutant is an adenine auxotroph and is unable to successfully cause infections in a murine model of virulence. Plate assays revealed that production of a number of virulence factors essential for dissemination and survival of C. neoformans in a host environment was compromised even with the addition of exogenous adenine. Purified recombinant C. neoformans ADS lyase shows catalytic activity similar to its human counterpart, and its crystal structure, the first fungal ADS lyase structure determined, shows a high degree of structural similarity to that of human ADS lyase. Two potentially important amino acid differences are identified in the C. neoformans crystal structure, in particular a threonine residue that may serve as an additional point of binding for a fungal enzyme-specific inhibitor. Besides serving as an antimicrobial target, C. neoformans ADS lyase inhibitors may also serve as potential therapeutics for metabolic disease; rather than disrupt ADS lyase, compounds that improve the stability the enzyme may be used to treat ADS Lyase Deficiency disease.

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Promoting Mental Health in Italian Middle and High School: A Pilot Study

Aim. In Italy, a handbook has been developed based on the principles of cooperative learning, life skills, self-effectiveness, and problem-solving at high school level. Early studies have shown the handbook’s effectiveness. It has been hypothesized that the revised handbook could be more effective in middle schools. Method. The study design is a “pre- and posttest” that compares the results obtained from 91 students of the high schools with those of the 38 students from middle schools. The assessment was made through “self-reporting” questionnaires of (a) learning skills including problem-solving and (b) perceived self-efficacy in managing emotions, dysfunctional beliefs, and unhealthy behaviours (i.e., drinking/smoking). Results. Significant improvements were observed in both groups with the exceptions of perceived self-efficacy in managing emotions. The improvement of dysfunctional beliefs and the learning of problem-solving skills were better in middle schools. Conclusion. The results confirm the authors’ hypothesis that the use of this approach is much more promising in middle school.

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In Vivo 3T Magnetic Resonance Imaging Using a Biologically Specific Contrast Agent for Prostate Cancer: A Nude Mouse Model

We characterized in vivo a functional superparamagnetic iron-oxide magnetic resonance contrast agent that shortens the relaxation time in magnetic resonance imaging (MRI) of prostate cancer xenografts. The agent was developed by conjugating Molday ION™ carboxyl-6 (MIC6), with a deimmunized mouse monoclonal antibody (muJ591) targeting prostate-specific membrane antigen (PSMA). This functional contrast agent could be used as a noninvasive method to detect prostate cancer cells that are PSMA positive and more readily differentiate them from surrounding tissues for treatment. The functional contrast agent was injected intravenously into mice and its effect was compared to both MIC6 (without conjugated antibody) and phosphate-buffered saline (PBS) injection controls. MR imaging was performed on a clinical 3T MRI scanner using a multiecho spin echo (MESE) sequence to obtain relaxation time values. Inductively coupled plasma atomic emission spectroscopy was used to confirm an increase in elemental iron in injected mice tumours relative to controls. Histological examination of H&E stained tissues showed normal morphology of the tissues collected.

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Fresh Snack Food Channel Evaluation Model for Integrating Customers’ Perception of Transaction Costs in Taiwan

The primary purpose of this study was to explore how food dealers develop methods that facilitate transaction efficiency and how they select the optimal food channels. This study establishes a model according to the impact of transaction cost factors on consumers’ decision-making regarding purchase of fresh snack foods. Using fresh snack foods in Taiwan as an example, this study employed a fuzzy analytic network process to solve decision-making problems with multiple criteria by comparing the interaction between each transaction cost factor to obtain the factor weightings as well as the weightings of the transaction costs at each decision stage. This study found that food safety assurance and providing sufficient nutrition information were the most essential topics; thus, the optimal choice for snack food producers is to develop retail outlets. This study construction process proposed is innovative and operational, and the results may provide a reference for snack food dealers or microfood enterprises to assist them in developing their food channels.

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Corrigendum to “A Study on the Combustion Performance of Diesel Engines with O2 and CO2 Suction”

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Small Engines as Bottoming Cycle Steam Expanders for Internal Combustion Engines

Heat recovery bottoming cycles for internal combustion engines have opened new avenues for research into small steam expanders (Stobart and Weerasinghe, 2006). Dependable data for small steam expanders will allow us to predict their suitability as bottoming cycle engines and the fuel economy achieved by using them as bottoming cycles. Present paper is based on results of experiments carried out on small scale Wankel and two-stroke reciprocating engines as air expanders and as steam expanders. A test facility developed at Sussex used for measurements is comprised of a torque, power and speed measurements, electronic actuation of valves, synchronized data acquisition of pressure, and temperatures of steam and inside of the engines for steam and internal combustion cycles. Results are presented for four engine modes, namely, reciprocating engine in uniflow steam expansion mode and air expansion mode and rotary Wankel engine in steam expansion mode and air expansion mode. The air tests will provide base data for friction and motoring effects whereas steam tests will tell how effective the engines will be in this mode. Results for power, torque, and diagrams are compared to determine the change in performance from air expansion mode to steam expansion mode.

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Surgical Orthodontic Treatment of a Patient Affected by Type 1 Myotonic Dystrophy (Steinert Syndrome)

Myotonic dystrophy, or Steinert’s disease, is the most common form of muscular dystrophy that occurs in adults. This multisystemic form involves the skeletal muscles but affects also the eye, the endocrine system, the central nervous system, and the cardiac system. The weakness of the facial muscles causes a characteristic facial appearance frequently associated with malocclusions. Young people with myotonic dystrophy, who also have severe malocclusions, have bad oral functions such as chewing, breathing, and phonation. We present a case report of a 15-year-old boy with anterior open bite, upper and lower dental crowding, bilateral crossbite, and constriction of the upper jaw with a high and narrow palate. The patient’s need was to improve his quality of life. Because of the severity of skeletal malocclusion, it was necessary to schedule a combined orthodontic and surgical therapy in order to achieve the highest aesthetic and functional result. Although therapy caused an improvement in patient’s quality of life, the clinical management of the case was hard. The article shows a balance between costs and benefits of a therapy that challenges the nature of the main problem of the patient, and it is useful to identify the most appropriate course of treatment for similar cases.

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Combining Carcinoembryonic Antigen and Platelet to Lymphocyte Ratio to Predict Brain Metastasis of Resected Lung Adenocarcinoma Patients

We aimed to evaluate the role of pretreatment carcinoembryonic antigen (CEA) and platelet to lymphocyte ratio (PLR) in predicting brain metastasis after radical surgery for lung adenocarcinoma patients. The records of 103 patients with completely resected lung adenocarcinoma between 2013 and 2014 were reviewed. Clinicopathologic characteristics of these patients were assessed in the Cox proportional hazards regression model. Brain metastasis occurred in 12 patients (11.6%). On univariate analysis, N2 stage (P = 0.013), stage III (P = 0.016), increased CEA level (P = 0.006), and higher PLR value (P = 0.020) before treatment were associated with an increased risk of developing brain metastasis. In multivariate model analysis, CEA above 5.2 ng/mL (P = 0.014) and PLR ≥ 120 (P = 0.036) remained as the risk factors for brain metastasis. The combination of CEA and PLR was superior to CEA or PLR alone in predicting brain metastasis according to the receiver operating characteristic (ROC) curve analysis (area under ROC curve, AUC 0.872 versus 0.784 versus 0.704). Pretreatment CEA and PLR are independent and significant risk factors for occurrence of brain metastasis in resected lung adenocarcinoma patients. Combining these two factors may improve the predictability of brain metastasis.

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Agroforestry and Management of Trees in Bunya County, Mayuge District, Uganda

Woody plant resources continue to disappear in anthropogenic landscapes in Uganda. To slow down further loss of these resources requires the collaboration of farmers in tree planting in agroforestry systems. Tree planting interventions with the collaboration of farmers require a good understanding of tree management practices as well as trees that best satisfy farmers’ needs. We carried out this research to determine (1) the most preferred tree species and reasons why they are preferred, (2) the species conservation statuses, and (3) existing tree management practices and challenges to tree planting. Fourteen priority species valued because they yield edible fruits and timber have been prioritised in this study. Farmers are interested in managing trees but are constrained by many factors, key among which is scarcity of land and financial capital to manage tree planting. Trees are managed in crop fields and around the homestead. From farmers’ reports, the highly valued species are increasing in the landscape. In conclusion, the potential to manage trees in agroforestry systems exists but is hampered by many challenges. Secondly, the liking of trees that supply edible fruits seems to support the welfare maximisation theory which ideally states that rural people manage trees with the aim of having regular access to products that satisfy their household needs and not for income generation.

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Femoral nerve and lumbar plexus injury after minimally invasive lateral retroperitoneal transpsoas approach: electrodiagnostic prognostic indicators and a roadmap to recovery

Abstract

Injury to the lumbosacral (LS) plexus is a well-described complication after lateral retroperitoneal transpsoas approaches to the spine. The prognosis for functional recovery after lumbosacral plexopathy or femoral/obturator neuropathy is unclear. We designed a retrospective case-control study with patients undergoing one-level lateral retroperitoneal transpsoas lumbar interbody fusion (LLIF) between January 2011 and June 2016 to correlate electrodiagnostic assessments (EDX) to physiologic concepts of nerve injury and reinnervation, and attempt to build a timeline for patient evaluation and recovery. Cases with post-operative obturator or femoral neuropathy were identified. Post-operative MRI, nerve conduction studies (NCS), electromyography (EMG), and physical examinations were performed at intervals to assess clinical and electrophysiologic recovery of function. Two hundred thirty patients underwent LLIF. Six patients (2.6%) suffered severe femoral or femoral/obturator neuropathy. Five patients (2.2%) had immediate post-operative weakness. One of the six patients developed delayed weakness due to a retroperitoneal hematoma. Five out of six patients (83%) demonstrated EDX findings at 6 weeks consistent with axonotmesis. All patients improved to at least MRC 4/5 within 12 months of injury. In conclusion, neurapraxia is the most common LS plexus injury, and complete recovery is expected after 3 months. Most severe nerve injuries are a combination of neurapraxia and variable degrees of axonotmesis. EDX performed at 6 weeks and 3, 6, and 9 months provides prognostic information for recovery. In severe injuries of proximal femoral and obturator nerves, observation of proximal to distal progression of small-amplitude, short-duration (SASD) motor unit potentials may be the most significant prognostic indicator.

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Navigation-guided clipping of a de novo aneurysm associated with superficial temporal artery-middle cerebral artery bypass combined with indirect pial synangiosis in a patient with moyamoya disease

Abstract

De novo aneurysms associated with superficial temporal artery (STA)-middle cerebral artery (MCA) bypass are an extremely rare complication of direct revascularization surgery for moyamoya disease (MMD). The basic pathology of MMD includes fragility of the intracranial arterial wall characterized by medial layer thinness and waving of the internal elastic lamina. However, the incidence of newly formed aneurysms at the site of anastomosis currently remains unknown. Among 317 consecutive direct/indirect combined revascularization surgeries performed for MMD, we encountered a 52-year-old woman manifesting a de novo aneurysm adjacent to the site of anastomosis 11 years after successful STA-MCA bypass with encephalo-duro-myo-synangiosis (EDMS). Although the patient remained asymptomatic, the aneurysm gradually increased in diameter to more than 6 mm with the formation of a daughter sac, and a computational fluid dynamic study revealed low wall shear stress at the aneurysm dome. The patient underwent microsurgical clipping of the aneurysm using a neuro-navigation system that permitted the minimally invasive dissection of the temporal muscle flap used for EDMS at the site of the aneurysm without affecting pial synangiosis. The aneurysm was successfully occluded using a titanium clip without complications. The postoperative course was uneventful, and the patient was discharged without neurological deficits. De novo aneurysms associated with STA-MCA bypass for MMD may be safely treated with microsurgical clipping, even in cases initially managed by a combined revascularization procedure that includes complex pial synangiosis. We recommend the application of the neuro-navigation system for the maximum preservation of pial synangiosis during this procedure.

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Improved performance of organic light-emitting diode with vanadium pentoxide layer on the FTO surface

Abstract

Vanadium pentoxide layer deposited on the fluorine-doped tin oxide (FTO) anode by vacuum deposition has been investigated in organic light-emitting diode (OLED). With 12 nm optimal thickness of \(\hbox {V}_{2}\hbox {O}_{5}\) , the luminance efficiency is increased by 1.66 times compared to the single FTO-based OLED. The improvement of current efficiency implies that there is a better charge injection and better controlling of hole current. To investigate the performance of OLED by the buffer layer, \(\hbox {V}_{2}\hbox {O}_{5}\) films of different thicknesses were deposited on the FTO anode and their J–V and L–V characteristics were studied. Further analysis was carried out by measuring sheet resistance, optical transmittance and surface morphology with the FE-SEM images. This result indicates that the \(\hbox {V}_{2}\hbox {O}_{5}\) (12 nm) buffer layer is a good choice for increasing the efficiency of FTO-based OLED devices within the tunnelling region. Here the maximum value of current efficiency is found to be 2.83 cd / A.

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Importance of polaron effects for charge carrier mobility above and below pseudogap temperature in superconducting cuprates

Abstract

Polaron effects and charge carrier mobility in high- \(T_\mathrm{c}\) cuprate superconductors (HTSCs) have been investigated theoretically. The appropriate Boltzmann transport equations under relaxation time approximation were used to calculate the mobility of polaronic charge carriers and bosonic Cooper pairs above and below the pseudogap (PG) temperature \(T^*\) . It is shown that the scattering of polaronic charge carriers and bosonic Cooper pairs at acoustic and optical phonons are responsible for the charge carrier mobility above and below the PG temperature. We show that the energy scales of the binding energies of large polarons and polaronic Cooper pairs can be identified by PG cross-over temperature on the cuprate phase diagram.

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Dynamics of N th-order rogue waves in ( $$2+1$$ 2 + 1 )-dimensional Hirota equation

Abstract

Inspired by the works of Ohta and Yang, we construct general high-order rogue wave solutions for the \((2+1)\) -dimensional Hirota equation using the bilinear transformation method. The formula of the solutions can be represented in terms of determinants. It is shown that the order of rogue waves will depend on the roots of determinants. These rogue waves are line rogue waves, which arise from the constant background with a line profile and then disappear into the constant background again. In addition, some interesting dynamic patterns of rogue waves are exhibited in the (x, y) and (x, t) planes.

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Measurement-based local quantum filters and their ability to transform quantum entanglement

Abstract

We introduce local filters as a means to detect the entanglement of bound entangled states which do not yield to detection by witnesses based on positive maps which are not completely positive. We demonstrate how such non-detectable bound entangled states can be locally filtered into detectable bound entangled states. Specifically, we show that a bound entangled state in the orthogonal complement of the unextendible product bases (UPB), can be locally filtered into another bound entangled state that is detectable by the Choi map. We reinterpret these filters as local measurements on locally extended Hilbert spaces. We give explicit constructions of a measurement-based implementation of these filters for \(2 \otimes 2\) and \(3 \otimes 3\) systems. This provides us with a physical mechanism to implement such local filters.

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Nonplanar electrostatic shock waves in an opposite polarity dust plasma with nonextensive electrons and ions

Abstract

A rigorous theoretical investigation has been carried out on the propagation of nonplanar (cylindrical and spherical) dust-acoustic shock waves (DASHWs) in a collisionless four-component unmagnetized dusty plasma system containing massive, micron-sized, positively and negatively charged inertial dust grains along with q (nonextensive) distributed electrons and ions. The well-known reductive perturbation technique has been used to derive the modified Burgers equation (which describes the shock wave properties) and its numerical solution. It has been observed that the effects of charged dust grains of opposite polarity, nonextensivity of electrons and ions, and different dusty plasma parameters have significantly modified the fundamental properties (viz., polarity, amplitude, width, etc.) of the shock waves. The properties of DASHWs in nonplanar geometry are found to be significantly different from those in one-dimensional planar geometry. The findings of our results from this theoretical investigation may be useful in understanding the nonlinear features of localized electrostatic disturbances in both space and laboratory dusty plasmas.

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Quark number density and susceptibility calculation under one-loop correction in the mean-field potential

Abstract

We calculate quark number density and susceptibility under one-loop correction in the mean-field potential. The calculation shows continuous increase in the number density and susceptibility up to the temperature  \(T=0.4\) GeV. Then the values of number density and susceptibility approach the very weakly result with higher values of temperature. The result indicates that the calculated values fit well with increase in temperature to match the lattice QCD simulations of the same quantities.

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Flexible Multiferroic Bulk Heterojunction with Giant Magnetoelectric Coupling via van der Waals Epitaxy

ACS Nano

DOI: 10.1021/acsnano.7b02102

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Nanomechanically Visualizing Drug–Cell Interaction at the Early Stage of Chemotherapy

ACS Nano

DOI: 10.1021/acsnano.7b02376

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Berberine regulates the protein expression of multiple tumorigenesis-related genes in hepatocellular carcinoma cell lines

Hepatocellular carcinoma (HCC) is the seventh most common malignancy and the third leading cause of cancer-related death worldwide with an extremely grim prognosis. Berberine (BBR) has been found to inhibit pr...

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Similar cardiometabolic effects of high- and moderate-intensity training among apparently healthy inactive adults: a randomized clinical trial

Metabolic syndrome (MetS) increases the risk of morbidity and mortality from cardiovascular disease, and exercise training is an important factor in the treatment and prevention of the clinical components of M...

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Benefits of local tumor excision and pharyngectomy on the survival of nasopharyngeal carcinoma patients: a retrospective observational study based on SEER database

There is ongoing debate about surgery of primary site in nasopharyngeal carcinoma patients.

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Non-caloric sweetener provides magnetic resonance imaging contrast for cancer detection

Image contrast enhanced by exogenous contrast agents plays a crucial role in the early detection, characterization, and determination of the precise location of cancers. Here, we investigate the feasibility of...

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Differential expression of microRNAs following cardiopulmonary bypass in children with congenital heart diseases

Children with congenital heart defects (CHDs) are at high risk for myocardial failure after operative procedures with cardiopulmonary bypass (CPB). Recent studies suggest that microRNAs (miRNA) are involved in...

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Basal subtype is predictive for response to cetuximab treatment in patient derived xenografts of squamous cell head and neck cancer

Abstract

Cetuximab is the single targeted therapy approved for the treatment of head and neck cancer (HNSCC). Predictive biomarkers have not been established and patient stratification based on molecular tumor profiles has not been possible. Since EGFR pathway activation is pronounced in basal subtype, we hypothesized this activation could be a predictive signature for an EGFR directed treatment. From our patient derived xenograft platform of HNSCC, 28 models were subjected to Affymetrix gene expression studies on HG U133+ 2.0. Based on the expression of 821 genes, the subtype of each of the 28 models was determined by integrating gene expression profiles through centroid-clustering with previously published gene expression data by Keck et al. The models were treated in groups of 5-6 animals with docetaxel, cetuximab, everolimus, cis- or carboplatin and 5-fluorouracil. Response was evaluated by comparing tumor volume at treatment initiation and after three weeks of treatment (RTV). Tumors distributed over the 3 signature-defined subtypes: 5 mesenchymal/inflamed phenotype (MS), 15 basal type (BA), 8 classical type (CL). Cluster analysis revealed a strong correlation between response to cetuximab and the basal subtype. RTV MS 3.32 vs BA 0.78 (MS vs BA, unpaired t test p0.0002). Cetuximab responders were distributed as following: 1/5 in MS, 5/8 in CL and 13/15 in the BA group. Activity of classical chemotherapies did not differ between the subtypes. In conclusion basal subtype was associated with response to EGFR directed therapy in head and neck squamous cell cancer patient derived xenografts. This article is protected by copyright. All rights reserved.

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Risk Stratification and Long-term Risk Prediction of E6 Oncoprotein in a Prospective Screening Cohort in China

Abstract

E6 oncoprotein is a necessary agent of HPV driven oncogenic transformation. This study is aimed at evaluating the risk stratification potency of HPV 16/18 E6 oncoprotein (E6) as a triage method for HPV positivity. Moreover, it also acts as a predictor of cervical intraepithelial neoplasia grade 3 or worse (CIN3+). The screening cohort of 1,997 women was followed for a 15 year period in approximate five-year intervals. Participants were concurrently screened by HPV DNA testing (HC2), liquid based cytology (LBC), visual inspection with acetic acid (VIA), and were referred to colposcopy and biopsy if any tests reflected positive. E6 was performed on cervical samples collected from this cohort in 2005 and 2014. The ability of E6 to predict CIN3+ risk after the five and ten year interval was evaluated. Among HPV positive women in 2005, E6 indicated the lowest positive rate (9.9%) compared to LBC (48.4%) and VIA (28.0%), however, a higher prevalence rate (10.3%) and ten year cumulative incidence rate (53.0%) of CIN3+ were detected among women who were E6 positive. Meanwhile, only approximately 4.2% and 2.9% of women with abnormal LBC and positive VIA were diagnosed as prevalent CIN3+ in 2005, 23.0% and 16.5% developed to CIN3+ after year ten, respectively. Strong associations were found between precedent and subsequent HPV persistence and E6 oncoprotein expression (OR_adjusted=40.0 and 21.2 respectively). E6 oncoprotein can serve as a low-cost, highly specific, strongly indicative point-of-care method in the triage and treatment of HPV positive women. This article is protected by copyright. All rights reserved.

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What has preoperative radio(chemo)therapy brought to localized rectal cancer patients in terms of perioperative and long-term outcomes over the past decades? A systematic review and meta-analysis based on 41,121 patients

Abstract

We asked what preoperative radiotherapy/chemoradiotherapy (PRT/PCRT) has brought to patients in terms of perioperative and long-term outcomes over the past decades. A systematic review and meta-analysis was conducted using PubMed, Embase and Web of Science databases. All original comparative studies published in English that were related to PRT/PCRT and surgical resection and which analyzed survival, postoperative and quality of life outcomes were included. Data synthesis and statistical analysis were carried out using Stata software. Data from 106 comparative studies based on 80 different trials enrolling 41,121 patients were included in our study. Based on our overall analyses, PRT/PCRT significantly improved patients' local recurrence-free survival (LRFS), but neither overall survival (OS) nor metastasis-free survival (MFS) showed improvement. In addition, PRT significantly increased the postoperative morbidity and mortality but PCRT did not have a significant effect. Furthermore, PRT/PCRT significantly increased the risk of postoperative wound complications but not anastomotic leakage and bowel obstruction. Our comprehensive subgroup analyses further supported the aforementioned results. Meanwhile, long-term anorectal symptoms (impaired squeeze pressures, use of pads, incontinence and urgency) and erectile dysfunction were also significantly increased in patients after PRT/PCRT. The benefits of PRT/PCRT as applied over the last several decades have not been sufficient to improve OS. Metastases of primary tumor and postoperative adverse effects were the two primary obstacles for an improved OS. In fact, the greatest advantage of PRT/PCRT is still local tumor control and a significantly improved LRFS. This article is protected by copyright. All rights reserved.

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Combination of chemotherapy and gefitinib as first-line treatment for patients with advanced lung adenocarcinoma and sensitive EGFR mutations: A randomized controlled trial

Abstract

To explore the optimal treatment strategy for patients who harbor sensitive EGFR mutations, a head-to-head study was performed to compare chemotherapy and gefitinib in combination or with either agent alone as first-line therapy, in terms of efficacy and safety. A total 121 untreated patients with advanced lung adenocarcinoma who harbored sensitive EGFR mutations were randomly assigned to receive gefitinib combined with pemetrexed and carboplatin, pemetrexed plus carboplatin, or gefitinib alone. The progression-free survival (PFS) of patients in the combination group (17.5 months, 95% CI, 15.3–19.7) was longer than that of patients in the chemotherapy group (5.7 months, 95% CI, 5.2–6.3) or gefitinib (11.9 months, 95% CI, 9.1–14.6) group. The (hazard ratios) HRs of PFS for the combination group versus chemotherapy and gefitinib groups were 0.16 (95% CI, 0.09–0.29, P < 0.001) and 0.48 (95% CI, 0.29–0.78, P = 0.003), respectively. The overall response rate (ORR) in the combination therapy group, chemotherapy group, and the gefitinib group was 82.5%, 32.5%, and 65.9%, respectively. The combinational strategy resulted in longer overall survival (OS) than chemotherapy (HR = 0.46, P = 0.016) or gefitinib (HR = 0.36, P = 0.001) alone. Our finding suggested that treatment with pemetrexed plus carboplatin combined with gefitinib could provide better survival benefits for patients with lung adenocarcinoma harboring sensitive EGFR mutations. This article is protected by copyright. All rights reserved.

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