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https://www.readbyqxmd.com/read/28437851/fexofenadine-a-putative-in-vivo-p-glycoprotein-probe-fails-to-predict-clearance-of-the-substrate-tacrolimus-in-renal-recipients
#1
Thomas Vanhove, Thomas Bouillon, Henriëtte de Loor, Pieter Annaert, Dirk R J Kuypers
Whether combined use of probe drugs for CYP3A4 and P-glycoprotein can clarify the relative contribution of these proteins to pharmacokinetic variability of a dual substrate like tacrolimus has never been assessed. Seventy renal recipients underwent simultaneous 8-hour pharmacokinetic profiles for tacrolimus, the CYP3A4 probe midazolam and the putative P-glycoprotein probe fexofenadine. Patients were genotyped for polymorphisms in CYP3A5, CYP3A4, ABCB1, ABCC2 and SLCO2B1, -1B1 and 1B3. Carriers of the ABCB1 2677G>A polymorphism displayed lower fexofenadine Cmax (-66%; P=0...
April 24, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28437760/the-effects-of-object-height-and-visual-information-on-the-control-of-obstacle-crossing-during-locomotion-in-healthy-older-adults
#2
Sho Kunimune, Shuichi Okada
In order to safely avoid obstacles, humans must rely on visual information regarding the position and shape of the object obtained in advance. The present study aimed to reveal the duration of obstacle visibility necessary for appropriate visuomotor control during obstacle avoidance in healthy older adults. Participants included 13 healthy young women (mean age: 21.5±1.4years) and 15 healthy older women (mean age: 68.5±3.5years) who were instructed to cross over an obstacle along a pressure-sensitive pathway at a self-selected pace while wearing liquid crystal shutter goggles...
April 13, 2017: Gait & Posture
https://www.readbyqxmd.com/read/28437627/tumor-acidity-activatable-tat-targeted-nanomedicine-for-enlarged-fluorescence-magnetic-resonance-imaging-guided-photodynamic-therapy
#3
Meng Gao, Feng Fan, Dongdong Li, Yue Yu, Kuirong Mao, Tianmeng Sun, Haisheng Qian, Wei Tao, Xianzhu Yang
Nanoparticles simultaneously integrated the photosensitizers and diagnostic agents represent an emerging approach for imaging-guided photodynamic therapy (PDT). However, the diagnostic sensitivity and therapeutic efficacy of nanoparticles as well as the heterogeneity of tumors pose tremendous challenges for clinical imaging-guided PDT treatment. Herein, a polymeric nanoparticle with tumor acidity (pHe)-activatable TAT targeting ligand that encapsulates the photosensitizer chlorin e6 (Ce6) and chelates contrast agent Gd(3+) is successfully developed for fluorescence/magnetic resonance (MR) dual-model imaging-guided precision PDT...
April 18, 2017: Biomaterials
https://www.readbyqxmd.com/read/28437275/descemet-membrane-endothelial-keratoplasty-after-failed-descemet-stripping-without-endothelial-keratoplasty
#4
Rohini Rao, Durga S Borkar, Kathryn A Colby, Peter B Veldman
PURPOSE: To describe the clinical course, surgical experience, and postoperative outcomes of 3 patients with Fuchs endothelial dystrophy who underwent Descemet membrane endothelial keratoplasty (DMEK) after failed Descemet stripping without endothelial keratoplasty. METHODS: Three patients who underwent DMEK for management of persistent corneal edema after deliberate Descemet stripping in the setting of Fuchs endothelial dystrophy were identified. Patients were examined at day 1, week 1, and months 1, 3, and 6 after DMEK...
April 21, 2017: Cornea
https://www.readbyqxmd.com/read/28437001/tumor-associated-changes-in-intestinal-epithelial-cells-cause-local-accumulation-of-klrg1-gata3-regulatory-t-cells-in-mice
#5
Holger Meinicke, Anna Bremser, Maria Brack, Paulina Akeus, Claire Pearson, Samuel Bullers, Katrin Hoffmeyer, Marc P Stemmler, Marianne Quiding-Järbrink, Ana Izcue
CD4(+) Foxp3(+) regulatory T cells (Treg) include differentiated populations of effector Treg characterized by the expression of specific transcription factors. Tumors, including intestinal malignancies, often present with local accumulation of Treg that can prevent tumor clearance, but how tumor progression leads to Treg accumulation is incompletely understood. Here using genetically modified mouse models we show that ablation of E-cadherin, a process associated with epithelial to mesenchymal transition (EMT) and tumor progression, promotes the accumulation of intestinal Treg by the specific accumulation of the KLRG1(+) GATA3(+) Treg subset...
April 24, 2017: Immunology
https://www.readbyqxmd.com/read/28436958/local-clearance-of-senescent-cells-attenuates-the-development-of-post-traumatic-osteoarthritis-and-creates-a-pro-regenerative-environment
#6
Ok Hee Jeon, Chaekyu Kim, Remi-Martin Laberge, Marco Demaria, Sona Rathod, Alain P Vasserot, Jae Wook Chung, Do Hun Kim, Yan Poon, Nathaniel David, Darren J Baker, Jan M van Deursen, Judith Campisi, Jennifer H Elisseeff
Senescent cells (SnCs) accumulate in many vertebrate tissues with age and contribute to age-related pathologies, presumably through their secretion of factors contributing to the senescence-associated secretory phenotype (SASP). Removal of SnCs delays several pathologies and increases healthy lifespan. Aging and trauma are risk factors for the development of osteoarthritis (OA), a chronic disease characterized by degeneration of articular cartilage leading to pain and physical disability. Senescent chondrocytes are found in cartilage tissue isolated from patients undergoing joint replacement surgery, yet their role in disease pathogenesis is unknown...
April 24, 2017: Nature Medicine
https://www.readbyqxmd.com/read/28436939/an-inflammatory-bowel-disease-risk-variant-in-inava-decreases-pattern-recognition-receptor-induced-outcomes
#7
Jie Yan, Matija Hedl, Clara Abraham
Inflammatory bowel disease (IBD) is characterized by dysregulation in both cytokines and responses to intestinal microbes, and proper regulation of pattern recognition receptor (PRR) signaling is critical for intestinal immune homeostasis. Altered functions for the IBD risk locus containing rs7554511, which encompasses the C1orf106 gene (recently named INAVA), and roles for the protein encoded by the INAVA gene are unknown. Here, we investigated the role of INAVA and INAVA genotype in regulating PRR-initiated outcomes in primary human cells...
April 24, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28436712/disposition-and-metabolism-of-14-c-galunisertib-a-tgf-%C3%AE-ri-kinase-alk5-inhibitor-following-oral-administration-in-healthy-subjects-and-mechanistic-prediction-of-the-effect-of-itraconazole-on-galunisertib-pharmacokinetics
#8
Kenneth C Cassidy, Ivelina Gueorguieva, Colin Miles, Jessica Rehmel, Ping Yi, William J Ehlhardt
The disposition and metabolism of galunisertib (LY2157299 monohydrate, a TGF-βRI Kinase/ALK5 Inhibitor) was characterized following a single oral dose of 150 mg of [(14)C]-galunisertib (100 µCi) to six healthy human subjects. The galunisertib plasma half-life was 8.6 h, while the (14)C half-life was 10.0 h. Galunisertib was abundant in circulation (40.3% of the (14)C AUC0-24h), with 7 additional metabolites detected in plasma. Two metabolites LSN3199597 (M5, mono-oxidation), and M4 (glucuronide of M3) were the most abundant circulating metabolites (10...
April 24, 2017: Xenobiotica; the Fate of Foreign Compounds in Biological Systems
https://www.readbyqxmd.com/read/28436655/investigating-the-antibacterial-activity-of-biphenylthiazoles-against-methicillin-and-vancomycin-resistant-staphylococcus-aureus-mrsa-and-vrsa
#9
Mohamed Hagras, Haroon Mohammad, Mohamed S Mandour, Youssef A Hegazy, Adel Ghiaty, Mohamed N Seleem, Abdelrahman S Mayhoub
Phenylthiazoles were reported previously as a new scaffold with antibacterial activity against an array of multidrug-resistant staphylococci. However, their promising antibacterial activity was hampered in large part by their short half-life due to excessive hepatic clearance. Close inspection of the structure-activity-relationships (SAR) of the phenylthiazoles revealed two important structural features necessary for antibacterial activity (a nitrogenous and a lipophilic component). Incorporating the nitrogenous part within a pyrimidine ring resulted in analogues with a prolonged half-life, while the biphenyl moiety revealed the most potent analogue 1b...
April 24, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28436637/-research-progress-on-mechanism-of-nix-mediated-mitophagy
#10
Yanrong Zheng, Xiangnan Zhang, Zhong Chen
Autophagy is fundamental to maintain cellular homeostasis. As one kind of the most well-studied selective autophagy, autophagy of mitochondria (mitophagy)is crucial for the clearance of damaged mitochondria. Mitophagy dysfunction has been proved to be closely associated with many human diseases. Nix is a key protein for mitophagy during the maturation of reticulocytes. However, the detailed molecular mechanisms underlying Nix-mediated mitophagy are not fully understood. This article summarizes three possible working models of Nix in mitophagy induction...
January 25, 2017: Zhejiang da Xue Xue Bao. Yi Xue Ban, Journal of Zhejiang University. Medical Sciences
https://www.readbyqxmd.com/read/28436589/short-chain-fatty-acids-augment-rat-duodenal-mucosal-barrier-function
#11
Wan Salman Wan Saudi, Markus Sjöblom
Short-chain fatty acids (SCFAs) are produced by bacterial fermentation in the large intestine, particularly from diets containing fibres and carbohydrates. The small intestinal epithelium is exposed to SCFAs derived mainly from oral bacteria or food supplementation. Although luminal nutrients are important in regulation of intestinal functions the role of SCFAs in regulation of small intestinal mucosal barrier function and motility has not been fully described. The aim of the present study was to elucidate the effects of acetate and propionate on duodenal mucosal barrier function and motility...
April 24, 2017: Experimental Physiology
https://www.readbyqxmd.com/read/28436464/glucose-dependent-regulation-of-pregnane-x-receptor-is-modulated-by-amp-activated-protein-kinase
#12
Peter O Oladimeji, Wenwei Lin, C Trent Brewer, Taosheng Chen
Pregnane X receptor (PXR) is a xenobiotic receptor that regulates the detoxification and clearance of drugs and foreign compounds from the liver. There has been mounting evidence of crosstalk between the drug metabolism pathway and the energy metabolism pathway, but little is known about this cross-regulation. To further delineate the energy metabolism and drug metabolism crosstalk in this study, we exposed HepG2 cells to varying glucose concentrations. We observed that PXR activity was induced under high-glucose conditions...
April 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28436097/the-vaginal-microbiome-and-gynaecological-cancer-exercise-caution-when-considering-causation
#13
Neal C Ramchander, Emma J Crosbie
Genital infection with high-risk human papillomavirus (HPV) is extremely common in young, sexually active women, but most infections are transient and clear without ever causing disease. Persistent infection causes premalignant cervical intraepithelial neoplasia (CIN), which, if left untreated, can undergo malignant transformation and become invasive cancer. Cervical cancer is thus considered a late, rare consequence of persistent high-risk HPV infection (Crosbie et al. Lancet 2013; 382:889-99). Factors that influence the acquisition of genital HPV and the rate of its natural clearance are therefore important in the pathogenesis of cervical cancer...
April 24, 2017: BJOG: An International Journal of Obstetrics and Gynaecology
https://www.readbyqxmd.com/read/28435897/association-between-lactate-clearance-during-post-resuscitation-care-and-neurologic-outcome-in-cardiac-arrest-survivors-treated-with-targeted-temperature-management
#14
Jung Chang Kim, Byung Kook Lee, Dong Hun Lee, Yong Hun Jung, Yong Soo Cho, Sung Min Lee, Seung Joon Lee, Chi Ho Park, Kyung Woon Jeung
OBJECTIVE: We investigated the association between lactate clearance or serum lactate levels and neurologic outcomes or in-hospital mortality in cardiac arrest survivors who were treated with targeted temperature management (TTM). METHODS: A retrospective analysis of data from cardiac arrest survivors treated with TTM between 2012 and 2015 was conducted. Serum lactate levels were measured on admission and at 12, 24, and 48 hours following admission. Lactate clearance at 12, 24, and 48 hours was also calculated...
March 2017: Clinical and Experimental Emergency Medicine
https://www.readbyqxmd.com/read/28435870/nanoparticles-that-do-not-adhere-to-mucus-provide-uniform-and-long-lasting-drug-delivery-to-airways-following-inhalation
#15
Craig S Schneider, Qingguo Xu, Nicholas J Boylan, Jane Chisholm, Benjamin C Tang, Benjamin S Schuster, Andreas Henning, Laura M Ensign, Ethan Lee, Pichet Adstamongkonkul, Brian W Simons, Sho-Yu S Wang, Xiaoqun Gong, Tao Yu, Michael P Boyle, Jung Soo Suk, Justin Hanes
Mucoadhesive particles (MAP) have been widely explored for pulmonary drug delivery because of their perceived benefits in improving particle residence in the lungs. However, retention of particles adhesively trapped in airway mucus may be limited by physiologic mucus clearance mechanisms. In contrast, particles that avoid mucoadhesion and have diameters smaller than mucus mesh spacings rapidly penetrate mucus layers [mucus-penetrating particles (MPP)], which we hypothesized would provide prolonged lung retention compared to MAP...
April 2017: Science Advances
https://www.readbyqxmd.com/read/28435691/interrupting-antiretroviral-treatment-in-hiv-cure-research-scientific-and-ethical-considerations
#16
EDITORIAL
Samual A Garner, Stuart Rennie, Jintanat Ananworanich, Karine Dube, David M Margolis, Jeremy Sugarman, Randall Tressler, Adam Gilbertson, Liza Dawson
Over the past several years there has been intense activity directed at the possibility of achieving remission or eradication of HIV infection. Current assays for the measurement of latent HIV are insufficient to demonstrate complete clearance of replication-competent HIV. Therefore, the ultimate test for assessing whether investigational interventions have resulted in HIV remission or eradication is to interrupt standard antiretroviral therapy (ART) in a carefully controlled clinical trial setting. These procedures, known as analytic treatment interruptions (ATIs), raise important scientific and ethical questions...
April 1, 2017: Journal of Virus Eradication
https://www.readbyqxmd.com/read/28435533/discovery-of-antimalarial-azetidine-2-carbonitriles-that-inhibit-p-falciparum-dihydroorotate-dehydrogenase
#17
Micah Maetani, Nobutaka Kato, Valquiria A P Jabor, Felipe A Calil, Maria Cristina Nonato, Christina A Scherer, Stuart L Schreiber
Dihydroorotate dehydrogenase (DHODH) is an enzyme necessary for pyrimidine biosynthesis in protozoan parasites of the genus Plasmodium, the causative agents of malaria. We recently reported the identification of novel compounds derived from diversity-oriented synthesis with activity in multiple stages of the malaria parasite life cycle. Here, we report the optimization of a potent series of antimalarial inhibitors consisting of azetidine-2-carbonitriles, which we had previously shown to target P. falciparum DHODH in a biochemical assay...
April 13, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28435143/estimation-of-inter-individual-variability-of-pharmacokinetics-of-cyp2c9-substrates-in-humans
#18
Koji Chiba, Keiko Shimizu, Motohiro Kato, Taichi Miyazaki, Takaaki Nishibayashi, Kazuki Terada, Yuichi Sugiyama
The activity of metabolic enzymes varies across individuals and populations. Activity varies even among individuals sharing the same genotype. Genetic polymorphisms in CYP2C9 cause significant inter-individual variability in the metabolism of its substrates. However, the variability of CYP2C9 intrinsic hepatic clearance (CLint,h,CYP2C9) among subjects of the same genotype has not been reported. In this study, we estimated the coefficient of variation (CV) for the intrinsic hepatic clearance of tolbutamide by CYP2C9 for each CYP2C9 genotype using previously reported AUCs and oral clearance (CLoral) values in a Monte Carlo simulation with a dispersion model...
April 20, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28435051/akt1-nf%C3%AE%C2%BAb-signaling-pathway-activation-by-a-small-molecule-dma-confers-radioprotection-to-intestinal-epithelium-in-xenograft-model
#19
Vinod Tiwari, Mohammad Zahid Kamran, Atul Ranjan, Hemlata Nimesh, Manish Singh, Vibha Tandon
Normal tissue protection and recovery of radiation-induced damage are of paramount importance for development of radioprotector. Radioprotector which selectively protects normal tissues over cancerous tissues improves the therapeutic window of radiation therapy. In the present study, small bisbenzimidazole molecule, DMA (5-(4-methylpiperazin-1-yl)-2-[2'-(3,4-dimethoxy-phenyl)-5'-benzimidazolyl]-benzimidazole) was evaluated for in vivo radioprotective effects to selectively protect normal tissue over tumor with underlying molecular mechanism...
April 20, 2017: Free Radical Biology & Medicine
https://www.readbyqxmd.com/read/28434735/effects-of-graded-removal-of-lysine-from-an-intravenously-infused-amino-acid-mixture-on-lactation-performance-and-mammary-amino-acid-metabolism-in-lactating-goats
#20
C L Guo, Y T Li, X Y Lin, M D Hanigan, Z G Yan, Z Y Hu, Q L Hou, F G Jiang, Z H Wang
To investigate responses of milk protein synthesis and mammary AA metabolism to a graded decrease of postruminal Lys supply, 4 lactating goats fitted with jugular vein, mammary vein, and carotid artery catheters and transonic blood flow detectors on the external pudic artery were used in a 4 × 4 Latin square experiment. Goats were fasted for 24 h and then received a 9-h intravenous infusion of an AA mixture plus glucose. Milk yield was recorded and samples were taken in h 2 to 8 of the infusion period; a mammary biopsy was performed in the last hour...
April 20, 2017: Journal of Dairy Science
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