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https://www.readbyqxmd.com/read/28088839/pharmacokinetic-pharmacodynamic-modeling-of-the-pde4-inhibitor-tak-648-in-type-2-diabetes-early-translational-approaches-for-human-dose-prediction
#1
N Plock, S Vollert, M Mayer, G Hanauer, G Lahu
TAK-648 is a PDE4 inhibitor with demonstrated preclinical antidiabetic properties. Our objective was to develop a translational pharmacokinetic/pharmacodynamic (PK/PD) model for human type 2 diabetes (T2D) dose prediction using HbA1c results from a db/db mouse study. Estimated parameters in combination with tPDE4i values calculated for the clinical roflumilast dose of 500 μg were used to translate preclinical effects of TAK-648 to required exposure in humans. A first-in-human study with single TAK-648 doses of 0...
January 15, 2017: Clinical and Translational Science
https://www.readbyqxmd.com/read/28088793/hnrnp-l-mediates-bladder-cancer-progression-by-inhibiting-apoptotic-signaling-and-enhancing-mapk-signaling-pathways
#2
Daojun Lv, Huayan Wu, Rongwei Xing, Fangpeng Shu, Bin Lei, Chengyong Lei, Xumin Zhou, Bo Wan, Yu Yang, Liren Zhong, Xiangming Mao, Yaguang Zou
Heterogeneous nuclear ribonucleoprotein L (hnRNP-L) is a promoter of various kinds of cancers, but its actions in bladder cancer (BC) are unclear. In this study, we investigated the function and the underlying mechanism of hnRNP-L in bladder carcinogenesis. Our results demonstrated that enhanced hnRNP-L expression in BC tissues was associated with poor overall survival of BC patients. Depletion of hnRNP-L significantly suppressed cell proliferation in vitro and inhibited xenograft tumor growth in vivo. Furthermore, downregulation of hnRNP-L resulted in G1-phase cell cycle arrest and enhanced apoptosis accompanied by inhibition of EMT and cell migration...
January 11, 2017: Oncotarget
https://www.readbyqxmd.com/read/28088787/hint2-downregulation-promotes-colorectal-carcinoma-migration-and-metastasis
#3
Weihua Li, Shaoxin Cai, Le Wang, Changshun Yang, Biaohuan Zhou, Huan Wang
Histidine triad nucleotide-binding 2 (HINT2), a member of the histidine triad proteins family, sensitizes cells to apoptosis in hepatocellular carcinoma. Here, we showed that HINT2 expression is lower in primary colorectal cancer (CRC) and metastasis tissues than in normal colorectal tissues, and that HINT2 abundance is inversely correlated with CRC tumor stage. Treating CRC cells with 5-aza-2'-deoxycytidine, a demethylating agent, upregulated HINT2, suggesting HINT2 downregulation is caused by methylation of the gene promoter...
January 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28088785/the-igh-locus-3-cis-regulatory-super-enhancer-co-opts-aid-for-allelic-transvection
#4
Sandrine Le Noir, Brice Laffleur, Claire Carrion, Armand Garot, Sandrine Lecardeur, Eric Pinaud, Yves Denizot, Jane Skok, Michel Cogné
Immunoglobulin heavy chain (IgH) alleles have ambivalent relationships: they feature both allelic exclusion, ensuring monoallelic expression of a single immunoglobulin (Ig) allele, and frequent inter-allelic class-switch recombination (CSR) reassembling genes from both alleles. The IgH locus 3' regulatory region (3'RR) includes several transcriptional cis-enhancers promoting activation-induced cytidine deaminase (AID)-dependent somatic hypermutation (SHM) and CSR, and altogether behaves as a strong super-enhancer...
January 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/28088783/%C3%AE-asarone-blocks-7%C3%AE-hydroxycholesterol-exposed-macrophage-injury-through-blocking-elf2%C3%AE-phosphorylation-and-prompting-beclin-1-dependent-autophagy
#5
Sin-Hye Park, Min-Kyung Kang, Yean-Jung Choi, Yun-Ho Kim, Lucia Dwi Antika, Dong Yeon Kim, Eun-Jung Lee, Soon Sung Lim, Young-Hee Kang
Macrophage apoptosis is salient in advanced atherosclerotic lesions and is induced by several stimuli including endoplasmic reticulum (ER) stress. This study examined that α-asarone present in purple perilla abrogated macrophage injury caused by oxysterols via ER stress- and autophagy-mediated mechanisms. Nontoxic α-asarone at 1-20 μM attenuated 7β-hydroxycholesterol-induced activation of eukaryotic initiation factor 2α in macrophages leading to C/EBP homologous protein (CHOP) expression and apoptosis due to sustained ER stress...
January 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28088782/pde5-inhibitors-enhance-the-lethality-of-pemetrexed-sorafenib
#6
Laurence Booth, Jane L Roberts, Andrew Poklepovic, Paul Dent
The combination of pemetrexed and sorafenib has significant clinical activity against a wide variety of tumor types in patients and the present studies were performed to determine whether sildenafil enhances the killing potential of [pemetrexed + sorafenib]. In multiple genetically diverse lung cancer cell lines, sildenafil enhanced the lethality of [pemetrexed + sorafenib]. The three-drug combination reduced the activities of AKT, mTOR and STAT transcription factors; increased the activities of eIF2α and ULK-1; lowered the expression of MCL-1, BCL-XL, thioredoxin and SOD2; and increased the expression of Beclin1...
January 9, 2017: Oncotarget
https://www.readbyqxmd.com/read/28088762/the-super-n-motifs-model-a-novel-alignment-free-approach-for-representing-and-comparing-rna-secondary-structures
#7
Jean-Pierre Séhi Glouzon, Jean-Pierre Perreault, Shengrui Wang
MOTIVATION: Comparing ribonucleic acid (RNA) secondary structures of arbitrary size uncovers structural patterns that can provide a better understanding of RNA functions. However, performing fast and accurate secondary structure comparisons is challenging when we take into account the RNA configuration (i.e. linear or circular), the presence of pseudoknot and G-quadruplex (G4) motifs and the increasing number of secondary structures generated by high-throughput probing techniques. To address this challenge, we propose the super-n-motifs model based on a latent analysis of enhanced motifs comprising not only basic motifs but also adjacency relations...
January 14, 2017: Bioinformatics
https://www.readbyqxmd.com/read/28088726/fabrication-of-highly-hydrophilic-filter-using-natural-and-hydrothermally-treated-mica-nanoparticles-for-efficient-waste-oil-water-separation
#8
Udara Bimendra Gunatilake, Jayasundera Bandara
For the effective oil/water separation, a novel superhydrophilic (underwater superoleophobic) filter is fabricated with the naturally and hydrothermally treated mica particles. To fabricate a double layered filter, hydrothermally treated mica particles were initially electrodeposited on a stainless steel mesh and a natural mica particles were sprayed on the first hydrothermally deposited mica layer. The double layered mica coated membrane showed superamphiphilic and superhydrophilic/superoleophobic (contact angle >159°) characteristics in air and underwater respectively...
January 12, 2017: Journal of Environmental Management
https://www.readbyqxmd.com/read/28088722/in-situ-denitrification-and-dnra-rates-in-groundwater-beneath-an-integrated-constructed-wetland
#9
M M R Jahangir, O Fenton, C Müller, R Harrington, P Johnston, K G Richards
Evaluation of the environmental benefits of constructed wetlands (CWs) requires an understanding of their impacts on the groundwater quality under the wetlands. Empirical mass-balance (nitrogen in/nitrogen out) approaches for estimating nitrogen (N) removal in CWs do not characterise the final fate of N; where nitrate (NO3(-)-N) could be reduced to either ammonium (NH4(+)-N) or N2 with the potential for significant production of N2O. Herein, in situ denitrification and DNRA (dissimilatory nitrate reduction to ammonium) rates were measured in groundwater beneath cells of an earthen lined integrated constructed wetland (ICW, used to remove the nutrients from municipal wastewater) using the (15)N-enriched NO3(-)-N push-pull method...
January 7, 2017: Water Research
https://www.readbyqxmd.com/read/28088721/modeling-biosolids-drying-through-a-laminated-hydrophobic-membrane
#10
Solmaz Marzooghi, Chunjian Shi, Steven K Dentel, Paul T Imhoff
The adaptation of the membrane distillation process as a low-cost and sustainable approach to biosolids drying and stabilization is investigated, which may have application in container-based sanitation systems proposed in low-income urban regions. Three-layer laminated, breathable, hydrophobic membranes enclose the biosolids, facilitating drying but preventing transport of contaminants. The membranes used in this process are non-wetting with pore spaces that only allow vapor transport. Water vapor can be expelled due to a moderate vapor pressure gradient...
December 29, 2016: Water Research
https://www.readbyqxmd.com/read/28088719/low-temperature-mbbr-nitrification-microbiome-analysis
#11
Bradley Young, Robert Delatolla, Kevin Kennedy, Edith Laflamme, Alain Stintzi
This study aims to investigate post carbon removal moving bed biofilm reactor (MBBR) nitrification through the transition from 20 °C to 1 °C and during through long term operation at 1 °C. Four pilot nitrifying MBBR reactors were operated at various ammonia loading rates to elucidate the temperature effects on ammonia removal rates, cell viability and bacterial communities. The transition from 20 °C to 1 °C and during long term operation at 1 °C were modeled using Arrhenius temperature correction coefficients...
January 5, 2017: Water Research
https://www.readbyqxmd.com/read/28088707/dna-sensing-and-immune-responses-in-cancer-therapy
#12
REVIEW
Jian Qiao, Haidong Tang, Yang-Xin Fu
The identification of critical DNA sensors and their pathways has led to revealing the central role of DNA sensing in immune system. It has been initially demonstrated that DNA sensing and immune responses have high impacts on the development and prevention of infection and inflammatory. In addition to toll-like receptor pathways, there is now also emerging evidence that cytosolic enzyme cyclic GMP-AMP synthase (cGAS) is essential for the recognition of not only pathogen-derived DNA but also tumor DNA for innate sensing...
January 12, 2017: Current Opinion in Immunology
https://www.readbyqxmd.com/read/28088705/ultrasonic-compaction-of-granular-geological-materials
#13
Andrew Feeney, Sakalima Sikaneta, Patrick Harkness, Margaret Lucas
It has been shown that the compaction of granular materials for applications such as pharmaceutical tableting and plastic moulding can be enhanced by ultrasonic vibration of the compaction die. Ultrasonic vibrations can reduce the compaction pressure and increase particle fusion, leading to higher strength products. In this paper, the potential benefits of ultrasonics in the compaction of geological granular materials in downhole applications are explored, to gain insight into the effects of ultrasonic vibrations on compaction of different materials commonly encountered in sub-sea drilling...
January 5, 2017: Ultrasonics
https://www.readbyqxmd.com/read/28088702/the-social-nature-of-overimitation-insights-from-autism-and-williams-syndrome
#14
Giacomo Vivanti, Darren R Hocking, Peter Fanning, Cheryl Dissanayake
When imitating novel actions, typically developing preschoolers often copy components of the demonstration that are unrelated to the modeled action's goal, a phenomenon known as 'overimitation'. According to the social motivation account, overimitation fulfills social affiliation motives (i.e., the imitator's drive to experience social connectedness with the demonstrator and the social context). Conversely, according to the social-cognitive account, overimitation reflects overattribution of causal relevance (i...
January 12, 2017: Cognition
https://www.readbyqxmd.com/read/28088698/metformin-enhancing-the-antitumor-efficacy-of-carboplatin-against-ehrlich-solid-carcinoma-grown-in-diabetic-mice-effect-on-igf-1-and-tumoral-expression-of-igf-1-receptors
#15
Dina M Abo-Elmatty, Eman A Ahmed, Mona K Tawfik, Seham A Helmy
Diabetes has been listed as a risk factor for various types of cancer. Cancer cell development can be promoted by increased levels of IGF-1 and hyperinsulinemia that are associated with diabetes type II. Metformin is an anti-diabetic agent and its potential antitumor impact has become the objective of numerous studies. In this vein, we hypothesize that using metformin in diabetes type II mice may synergistic with carboplatin for reducing the risk of cancer. Therefore, the study aimed to evaluate the in vivo antitumor activity of metformin against solid EAC tumor growth in female diabetic mice and its potential pro-apoptotic and anti-proliferative effects with clarification of its inconclusive biological mechanisms...
January 12, 2017: International Immunopharmacology
https://www.readbyqxmd.com/read/28088693/reinforcement-of-a-pmma-resin-for-interim-fixed-prostheses-with-silica-nanoparticles
#16
Marianthi Topouzi, Eleana Kontonasaki, Dimitrios Bikiaris, Lambrini Papadopoulou, Konstantinos M Paraskevopoulos, Petros Koidis
PURPOSE: Fractures in long span provisional/interim restorations are a common complication. Adequate fracture toughness is necessary to resist occlusal forces and crack propagation, so these restorations should be constructed with materials of improved mechanical properties. The aim of this study was to investigate the possible reinforcement of neat silica nanoparticles and trietoxyvinylsilane-modified silica nanoparticles in a PMMA resin for fixed interim restorations. MATERIALS AND METHODS: Composite PMMA-Silica nanoparticles powders were mixed with PMMA liquid and compact bar shaped specimens were fabricated according to the British standard BS EN ISO 127337:2005...
January 9, 2017: Journal of the Mechanical Behavior of Biomedical Materials
https://www.readbyqxmd.com/read/28088679/post-event-processing-in-social-anxiety-disorder-examining-the-mediating-roles-of-positive-metacognitive-beliefs-and-perceptions-of-performance
#17
Dubravka Gavric, David A Moscovitch, Karen Rowa, Randi E McCabe
BACKGROUND: Post-event processing (PEP) is defined as repetitive negative thinking following anxiety provoking social events. PEP is thought to maintain anxiety symptoms in Social Anxiety Disorder (SAD) but little is known about the specific factors that contribute to the maintenance of PEP. AIMS: The current study investigated how perceptions of performance and positive metacognitive beliefs might contribute to the persistence of PEP. METHOD: Participants with SAD (n = 24) as well as anxious (n = 24) and healthy (n = 25) control participants completed a standardized social performance task in the lab...
January 4, 2017: Behaviour Research and Therapy
https://www.readbyqxmd.com/read/28088671/melatonin-attenuates-titanium-particle-induced-osteolysis-via-activation-of-wnt-%C3%AE-catenin-signaling-pathway
#18
Zichuan Ping, Xuanyang Hu, Liangliang Wang, Jiawei Shi, Yunxia Tao, Xiexing Wu, Zhenyang Hou, Xiaobin Guo, Wen Zhang, Huilin Yang, Yaozeng Xu, Zhirong Wang, Dechun Geng
: Wear debris-induced inhibition of bone regeneration and extensive bone resorption were common features in peri-prosthetic osteolysis (PPO). Here, we investigated the effect of melatonin on titanium particle-stimulated osteolysis in a murine calvariae model and mouse-mesenchymal-stem cells (mMSCs) culture system. Melatonin inhibited titanium particle-induced osteolysis and increased bone formation at osteolytic sites, confirmed by radiological and histomorphometric data. Furthermore, osteoclast numbers decreased dramatically in the low- and high-melatonin administration mice, as respectively, compared with the untreated animals...
January 11, 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/28088669/micro-mechanical-properties-of-the-tendon-to-bone-attachment
#19
Alix C Deymier, Yiran An, John J Boyle, Andrea G Schwartz, Victor Birman, Guy M Genin, Stavros Thomopoulos, Asa H Barber
: The tendon-to-bone attachment (enthesis) is a complex hierarchical tissue that connects stiff bone to compliant tendon. The attachment site at the micrometer scale exhibits gradients in mineral content and collagen orientation, which likely act to minimize stress concentrations. The physiological micromechanics of the attachment thus define resultant performance, but difficulties in sample preparation and mechanical testing at this scale have restricted understanding of structure-mechanical function...
January 11, 2017: Acta Biomaterialia
https://www.readbyqxmd.com/read/28088668/near-infrared-light-triggered-drug-delivery-system-for-higher-efficacy-of-combined-chemo-photothermal-treatment
#20
Yi Chen, Haohuan Li, Yueyang Deng, Haifeng Sun, Xue Ke, Tianyuan Ci
: The combination of chemotherapy and photothermal therapy is a promising strategy for cancer treatment. In the present study, indocyanine green (ICG), a widely used near-infrared (NIR) dye in photothermal therapy, and chemotherapeutic drug-doxorubicin (DOX) were loaded within the nanoparticles of novel designed arylboronic ester and cholesterol modified hyaluronic acid (PPE-Chol1-HA), denoted as PCH-DI. We take advantage of reactive oxygen species (ROS) production capability of ICG and ROS-sensitivity of arylboronic ester to realize controllable drug release...
January 11, 2017: Acta Biomaterialia
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