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  • 1
    Publication Date: 2018-11-16
    Description: Purpose: On the basis of the identified stress-independent cellular functions of activating transcription factor 4 (ATF4), we reported enhanced ATF4 levels in MCF10A cells treated with TGFβ1. ATF4 is overexpressed in patients with triple-negative breast cancer (TNBC), but its impact on patient survival and the underlying mechanisms remain unknown. We aimed to determine ATF4 effects on patients with breast cancer survival and TNBC aggressiveness, and the relationships between TGFβ and ATF4. Defining the signaling pathways may help us identify a cell signaling–tailored gene signature. Experimental Design: Patient survival data were determined by Kaplan–Meier analysis. Relationship between TGFβ and ATF4, their effects on aggressiveness (tumor proliferation, metastasis, and stemness), and the underlying pathways were analyzed in three TNBC cell lines and in vivo using patient-derived xenografts (PDX). Results: ATF4 overexpression correlated with TNBC patient survival decrease and a SMAD-dependent crosstalk between ATF4 and TGFβ was identified. ATF4 expression inhibition reduced migration, invasiveness, mammosphere-forming efficiency, proliferation, epithelial–mesenchymal transition, and antiapoptotic and stemness marker levels. In PDX models, ATF4 silencing decreased metastases, tumor growth, and relapse after chemotherapy. ATF4 was shown to be active downstream of SMAD2/3/4 and mTORC2, regulating TGFβ/SMAD and mTOR/RAC1–RHOA pathways independently of stress. We defined an eight-gene signature with prognostic potential, altered in 45% of 2,509 patients with breast cancer. Conclusions: ATF4 may represent a valuable prognostic biomarker and therapeutic target in patients with TNBC, and we identified a cell signaling pathway–based gene signature that may contribute to the development of combinatorial targeted therapies for breast cancer. Clin Cancer Res; 24(22); 5697–709. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 2
    Publication Date: 2018-03-06
    Description: Purpose: Chemoresistance in triple-negative breast cancer (TNBC) is associated with the activation of a survival mechanism orchestrated by the endoplasmic reticulum (EnR) stress response and by inducible nitric oxide synthase (iNOS). Our aim was to determine the effects of pharmacologic NOS inhibition on TNBC. Experimental Design: TNBC cell lines, SUM-159PT, MDA-MB-436, and MDA-MB-468, were treated with docetaxel and NOS inhibitor (L-NMMA) for 24, 48, and 72 hours. Apoptosis was assessed by flow cytometry using Annexin-V and propidium iodide. Western blot was used to assess ER stress and apoptosis, and rtPCR was used to evaluate s-XBP1. TNBC patient-derived xenografts (PDX) were treated either with vehicle, docetaxel, or combination therapy (NOS inhibition + docetaxel). Mouse weight and tumor volumes were recorded twice weekly. Docetaxel concentration was determined using mass spectrometry. To quantify proliferation and apoptosis, PDX tumor samples were stained using Ki67 and TUNEL assay. Results: In vitro, L-NMMA ameliorated the iNOS upregulation associated with docetaxel. Apoptosis increased when TNBC cells were treated with combination therapy. In TNBC PDXs, combination therapy significantly reduced tumor volume growth and increased survival proportions. In the BCM-5998 PDX model, intratumoral docetaxel concentration was higher in mice receiving combination therapy. Coupling docetaxel with NOS inhibition increased EnR-stress response via coactivation of ATF4 and CHOP, which triggered the pASK1/JNK proapoptotic pathway, promoting cleavage of caspases 3 and 9. Conclusions: iNOS is a critical target for docetaxel resistance in TNBC. Pharmacologic inhibition of NOS enhanced chemotherapy response in TNBC PDX models. Combination therapy may improve prognosis and prevent relapse in TNBC patients who have failed conventional chemotherapy. Clin Cancer Res; 24(5); 1152–62. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 3
    Publication Date: 2018-02-09
    Description: Objective A close relationship between gut microbiota and some chronic liver disorders has recently been described. Herein, we systematically performed a comparative analysis of the gut microbiome in primary biliary cholangitis (PBC) and healthy controls. Design We first conducted a cross-sectional study of 60 ursodeoxycholic acid (UDCA) treatment-naïve patients with PBC and 80 matched healthy controls. Second, an independent cohort composed of 19 treatment-naïve patients and 34 controls was used to validate the results. Finally, a prospective study was performed in a subgroup of 37 patients with PBC who underwent analysis before and after 6 months of UDCA treatment. Faecal samples were collected, and microbiomes were analysed by 16S ribosomal RNA gene sequencing. Results A significant reduction of within-individual microbial diversity was noted in PBC (p=0.03). A signature defined by decreased abundance of four genera and increased abundance of eight genera strongly correlated with PBC (area under curve=0.86, 0.84 in exploration and validation data, respectively). Notably, the abundance of six PBC-associated genera was reversed after 6 months of UDCA treatment. In particular, Faecalibacterium , enriched in controls, was further decreased in gp210-positive than gp210-negative patients (p=0.002). Of interest was the finding that the increased capacity for the inferred pathway, bacterial invasion of epithelial cells in PBC, highly correlated with the abundance of bacteria belonging to Enterobacteriaceae . Conclusions This study presents a comprehensive landscape of gut microbiota in PBC. Dysbiosis was found in the gut microbiome in PBC and partially relieved by UDCA. Our study suggests that gut microbiota is a potential therapeutic target and diagnostic biomarker for PBC.
    Keywords: Editor's choice
    Print ISSN: 0017-5749
    Electronic ISSN: 1468-3288
    Topics: Medicine
    Published by BMJ Publishing Group
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  • 4
    Publication Date: 2018-02-09
    Description: Objective To assess the impact of adjunctive antibiotic therapy on uncomplicated skin abscesses. Design Systematic review and network meta-analysis. Data sources Medline, Embase, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov. Study selection A BMJ Rapid Recommendation panel provided input on design, important outcomes and the interpretation of the results. Eligible randomised controlled trials (RCTs) included a comparison of antibiotics against no antibiotics or a comparison of different antibiotics in patients with uncomplicated skin abscesses, and reported outcomes prespecified by the linked guideline panel. Review methods Reviewers independently screened abstracts and full texts for eligibility, assessed risk of bias and extracted data. We performed random-effects meta-analyses that compared antibiotics with no antibiotics, along with a limited number of prespecified subgroup hypotheses. We also performed network meta-analysis with a Bayesian framework to compare effects of different antibiotics. Quality of evidence was assessed with The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Results Fourteen RCTs including 4198 patients proved eligible. Compared with no antibiotics, antibiotics probably lower the risk of treatment failure (OR 0.58, 95% CI 0.37 to 0.90; low quality), recurrence within 1 month (OR 0.48, 95% CI 0.30 to 0.77; moderate quality), hospitalisation (OR 0.55, 95% CI 0.32 to 0.94; moderate quality) and late recurrence (OR 0.64, 95% CI 0.48 to 0.85; moderate quality). However, relative to no use, antibiotics probably increase the risk of gastrointestinal side effects (trimethoprim and sulfamethoxazole (TMP-SMX): OR 1.28, 95% CI 1.04 to 1.58; moderate quality; clindamycin: OR 2.29, 95% CI 1.35 to 3.88; high quality) and diarrhoea (clindamycin: OR 2.71, 95% CI 1.50 to 4.89; high quality). Cephalosporins did not reduce the risk of treatment failure compared with placebo (moderate quality). Conclusions In patients with uncomplicated skin abscesses, moderate-to-high quality evidence suggests TMP-SMX or clindamycin confer a modest benefit for several important outcomes, but this is offset by a similar risk of adverse effects. Clindamycin has a substantially higher risk of diarrhoea than TMP-SMX. Cephalosporins are probably not effective.
    Keywords: Open access, Infectious diseases
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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  • 5
    Publication Date: 2018-06-26
    Description: The relation of local order to material properties in relaxor ferroelectrics The relation of local order to material properties in relaxor ferroelectrics, Published online: 25 June 2018; doi:10.1038/s41563-018-0112-7 How local order affects the excellent piezoelectric properties of Pb-based relaxor ferroelectrics is unclear, but neutron diffuse scattering shows that non-relaxor distortions are implicated, indicating the important role of oxygen atoms.
    Print ISSN: 1476-1122
    Electronic ISSN: 1476-4660
    Topics: Chemistry and Pharmacology , Mechanical Engineering, Materials Science, Production Engineering, Mining and Metallurgy, Traffic Engineering, Precision Mechanics , Natural Sciences in General , Physics
    Published by Springer Nature
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  • 6
    Publication Date: 2018-07-19
    Description: We present the first known fossilized snake embryo/neonate preserved in early Late Cretaceous (Early Cenomanian) amber from Myanmar, which at the time, was an island arc including terranes from Austral Gondwana. This unique and very tiny snake fossil is an articulated postcranial skeleton, which includes posterior precloacal, cloacal, and caudal vertebrae, and details of squamation and body shape; a second specimen preserves a fragment of shed skin interpreted as a snake. Important details of skeletal ontogeny, including the stage at which snake zygosphene-zygantral joints began to form along with the neural arch lamina, are preserved. The vertebrae show similarities to those of fossil Gondwanan snakes, suggesting a dispersal route of Gondwanan faunas to Laurasia. Finally, the new species is the first Mesozoic snake to be found in a forested environment, indicating greater ecological diversity among early snakes than previously thought.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 7
    Publication Date: 2018-08-16
    Description: Phosphorus (P) sorption in sediments plays a significant role in trophic status of a lake. This study investigated the characteristics of P sorption in sediments from three lakes with different trophic statuses (moderately eutrophic, lightly eutrophic and moderately trophic) through kinetic, batch equilibrium and thermodynamic experiments. Results show that pseudo-second-order kinetics best describe P sorption in sediments from the three lakes. Fitting by modified Langmuir and Freundlich isotherms indicates that the moderately trophic lake sediment has higher sorption capacity (maximum of 0.848 mg g –1 at 35°C) than the sediments of the other two lakes at different temperatures (5, 15, 25 and 35°C). Thermodynamic results indicate that the processes of P sorption of the three sediments are spontaneous, entropy-driven and endothermic reactions. The risk of P release in sediments was analysed according to the calculated results of isotherms combined with the change in P fraction. Sediments from the moderately eutrophic lake act as a source in summer. The lightly eutrophic and moderately trophic lakes act as sources in spring and winter, and a pool in summer and autumn, respectively. Furthermore, the amounts of reductant-soluble P, calcium-bound P and iron-bound P are significantly related to the sorption capacity of sediments from the three lakes ( p 〈 0.05). The different sediments have different P release risk, and P fraction in sediment is one of the significant factors of P sorption.
    Keywords: environmental science
    Electronic ISSN: 2054-5703
    Topics: Natural Sciences in General
    Published by Royal Society
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  • 8
    Publication Date: 2018-12-15
    Description: The edges of layered materials have unique properties that substantially differ from the body regions. In this work, we perform a systematic Raman study of the edges of various layered materials (MoS 2 , WS 2 , WSe 2 , PtS 2 , and black phosphorus). The Raman spectra of the edges feature newly observed forbidden Raman modes, which are originally undetectable from the body region. By selecting the edge type and the polarization directions of the incident and scattered light, all forbidden Raman modes are distinctly detected. Optical simulations show that the edges of layered materials drastically distort the electromagnetic fields of both the incident and scattered light, so that the light interacts with the edges in a distinct way, which differs from its interactions with the body regions.
    Electronic ISSN: 2375-2548
    Topics: Natural Sciences in General
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  • 9
    Publication Date: 2011-09-23
    Description: Common diseases are often complex because they are genetically heterogeneous, with many different genetic defects giving rise to clinically indistinguishable phenotypes. This has been amply documented for early-onset cognitive impairment, or intellectual disability, one of the most complex disorders known and a very important health care problem worldwide. More than 90 different gene defects have been identified for X-chromosome-linked intellectual disability alone, but research into the more frequent autosomal forms of intellectual disability is still in its infancy. To expedite the molecular elucidation of autosomal-recessive intellectual disability, we have now performed homozygosity mapping, exon enrichment and next-generation sequencing in 136 consanguineous families with autosomal-recessive intellectual disability from Iran and elsewhere. This study, the largest published so far, has revealed additional mutations in 23 genes previously implicated in intellectual disability or related neurological disorders, as well as single, probably disease-causing variants in 50 novel candidate genes. Proteins encoded by several of these genes interact directly with products of known intellectual disability genes, and many are involved in fundamental cellular processes such as transcription and translation, cell-cycle control, energy metabolism and fatty-acid synthesis, which seem to be pivotal for normal brain development and function.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Najmabadi, Hossein -- Hu, Hao -- Garshasbi, Masoud -- Zemojtel, Tomasz -- Abedini, Seyedeh Sedigheh -- Chen, Wei -- Hosseini, Masoumeh -- Behjati, Farkhondeh -- Haas, Stefan -- Jamali, Payman -- Zecha, Agnes -- Mohseni, Marzieh -- Puttmann, Lucia -- Vahid, Leyla Nouri -- Jensen, Corinna -- Moheb, Lia Abbasi -- Bienek, Melanie -- Larti, Farzaneh -- Mueller, Ines -- Weissmann, Robert -- Darvish, Hossein -- Wrogemann, Klaus -- Hadavi, Valeh -- Lipkowitz, Bettina -- Esmaeeli-Nieh, Sahar -- Wieczorek, Dagmar -- Kariminejad, Roxana -- Firouzabadi, Saghar Ghasemi -- Cohen, Monika -- Fattahi, Zohreh -- Rost, Imma -- Mojahedi, Faezeh -- Hertzberg, Christoph -- Dehghan, Atefeh -- Rajab, Anna -- Banavandi, Mohammad Javad Soltani -- Hoffer, Julia -- Falah, Masoumeh -- Musante, Luciana -- Kalscheuer, Vera -- Ullmann, Reinhard -- Kuss, Andreas Walter -- Tzschach, Andreas -- Kahrizi, Kimia -- Ropers, H Hilger -- England -- Nature. 2011 Sep 21;478(7367):57-63. doi: 10.1038/nature10423.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, 19857 Tehran, Iran.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21937992" target="_blank"〉PubMed〈/a〉
    Keywords: Brain/metabolism/physiology ; Cell Cycle ; Cognition Disorders/*genetics ; Consanguinity ; DNA Mutational Analysis ; Exons/genetics ; Gene Regulatory Networks ; Genes, Essential/genetics ; Genes, Recessive/*genetics ; *High-Throughput Nucleotide Sequencing ; Homozygote ; Humans ; Intellectual Disability/*genetics ; Metabolic Networks and Pathways ; Mutation/genetics ; Organ Specificity ; Synapses/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
    Publication Date: 2012-03-06
    Description: The Arabidopsis thaliana protein UVR8 is a photoreceptor for ultraviolet-B. Upon ultraviolet-B irradiation, UVR8 undergoes an immediate switch from homodimer to monomer, which triggers a signalling pathway for ultraviolet protection. The mechanism by which UVR8 senses ultraviolet-B remains largely unknown. Here we report the crystal structure of UVR8 at 1.8 A resolution, revealing a symmetric homodimer of seven-bladed beta-propeller that is devoid of any external cofactor as the chromophore. Arginine residues that stabilize the homodimeric interface, principally Arg 286 and Arg 338, make elaborate intramolecular cation-pi interactions with surrounding tryptophan amino acids. Two of these tryptophans, Trp 285 and Trp 233, collectively serve as the ultraviolet-B chromophore. Our structural and biochemical analyses identify the molecular mechanism for UVR8-mediated ultraviolet-B perception, in which ultraviolet-B radiation results in destabilization of the intramolecular cation-pi interactions, causing disruption of the critical intermolecular hydrogen bonds mediated by Arg 286 and Arg 338 and subsequent dissociation of the UVR8 homodimer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wu, Di -- Hu, Qi -- Yan, Zhen -- Chen, Wen -- Yan, Chuangye -- Huang, Xi -- Zhang, Jing -- Yang, Panyu -- Deng, Haiteng -- Wang, Jiawei -- Deng, XingWang -- Shi, Yigong -- R37 GM047850/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Feb 29;484(7393):214-9. doi: 10.1038/nature10931.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Tsinghua-Peking Center for Life Sciences, Center for Structural Biology, School of Life Sciences and School of Medicine, Tsinghua University, Beijing 100084, China.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22388820" target="_blank"〉PubMed〈/a〉
    Keywords: Arabidopsis/*chemistry ; Arabidopsis Proteins/*chemistry/*radiation effects ; Cations/chemistry ; Chromosomal Proteins, Non-Histone/*chemistry/*radiation effects ; Crystallography, X-Ray ; Light Signal Transduction/*radiation effects ; Models, Molecular ; Protein Conformation/radiation effects ; Protein Multimerization/radiation effects ; Tryptophan/chemistry/metabolism ; *Ultraviolet Rays
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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