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https://www.readbyqxmd.com/read/28806782/the-use-of-18f-fluoro-deoxy-glucose-positron-emission-tomography-18f-fdg-pet-as-a-non-invasive-pharmacodynamic-biomarker-to-determine-the-minimally-pharmacologically-active-dose-of-azd8835-a-novel-pi3k%C3%AE-inhibitor
#1
Juliana Maynard, Sally-Ann Emmas, Francois-Xavier Ble, Herve Barjat, Emily Lawrie, Urs Hancox, Urszula M Polanska, Alison Pritchard, Kevin Hudson
BACKGROUND: The phosphatidyl inositol 3 kinase (PI3K), AKT and mammalian target of rapamycin (mTOR) signal transduction pathway is frequently de-regulated and activated in human cancer and is an important therapeutic target. AZD8835 is a PI3K inhibitor, with selectivity against PI3K α and δ isoforms, which is currently in Phase 1 clinical trials. 18F-Fluoro-deoxy-glucose positron emission tomography (18F-FDG PET) is a non-invasive pharmacodynamic imaging biomarker that has become an integral part of drug development...
2017: PloS One
https://www.readbyqxmd.com/read/28806393/craf-gene-fusions-in-pediatric-low-grade-gliomas-define-a-distinct-drug-response-based-on-dimerization-profiles
#2
P Jain, T M Fierst, H J Han, T E Smith, A Vakil, P J Storm, A C Resnick, A J Waanders
Pediatric low-grade gliomas (PLGGs) are commonly associated with BRAF gene fusions that aberrantly activate the mitogen-activated protein kinase (MAPK) signaling pathway. This has led to PLGG clinical trials utilizing RAF- and MAPK pathway-targeted therapeutics. Whole-genome profiling of PLGGs has also identified rare gene fusions involving another RAF isoform, CRAF/RAF1, in PLGGs and cancers occuring in adults. Whereas BRAF fusions primarily dysregulate MAPK signaling, the CRAF fusions QKI-RAF1 and SRGAP3-RAF1 aberrantly activate both the MAPK and phosphoinositide-3 kinase/mammalian target of rapamycin (PI3K/mTOR) signaling pathways...
August 14, 2017: Oncogene
https://www.readbyqxmd.com/read/28806275/effects-of-creatine-and-carbohydrate-loading-on-cycling-time-trial-performance
#3
Kristyen A Tomcik, Donny M Camera, Julia L Bone, Megan L Ross, Nikki A Jeacocke, Bill Tachtsis, Joan Senden, Luc J C van Loon, John A Hawley, Louise M Burke
INTRODUCTION: Creatine- and carbohydrate-loading are dietary strategies used to enhance exercise capacity. This study examined the metabolic and performance effects of a combined creatine and CHO-loading regiment on time-trial (TT) cycling bouts. METHODS: Eighteen well-trained (~65mL[BULLET OPERATOR]kg[BULLET OPERATOR]min VO2peak) males completed three performance trials (PT) comprised of a 120-km cycling TT interspersed with alternating 1- and 4-km sprints (6 sprints each) performed every 10-km followed by an inclined ride to fatigue (~90% VO2peak)...
August 11, 2017: Medicine and Science in Sports and Exercise
https://www.readbyqxmd.com/read/28806133/autophagy-dictates-metabolism-and-differentiation-of-inflammatory-immune-cells
#4
Thomas Riffelmacher, Felix Clemens Richter, Anna Katharina Simon
The role of macroautophagy/autophagy, a conserved lysosomal degradation pathway, during cellular differentiation has been well studied over the last decade. Particularly, evidence for its role during immune cell differentiation is growing. Despite the description of a variety of dramatic immune phenotypes in tissue-specific autophagy knockout models, the underlying mechanisms are still under debate. One of the proposed mechanisms is the impact of autophagy on the altered metabolic states during immune cell differentiation...
August 14, 2017: Autophagy
https://www.readbyqxmd.com/read/28805979/effects-of-mtor-inhibition-on-cardiac-and-adipose-tissue-pathology-and-glucose-metabolism-in-rats-with-metabolic-syndrome
#5
Ayako Uchinaka, Mamoru Yoneda, Yuichiro Yamada, Toyoaki Murohara, Kohzo Nagata
The mammalian target of rapamycin (mTOR) is a regulator of metabolism and is implicated in pathological conditions such as obesity and diabetes. We aimed to investigate the role of mTOR in obesity. A new animal model of metabolic syndrome (MetS), named DahlS.Z-Lepr(fa) /Lepr(fa) (DS/obese) rats was established previously in our laboratory. In this study, we used this model to evaluate the effects of mTOR inhibition on cardiac and adipose tissue pathology and glucose metabolism. DS/obese rats were treated with the mTOR inhibitor, everolimus, (0...
August 2017: Pharmacology Research & Perspectives
https://www.readbyqxmd.com/read/28804535/hongjingtian-injection-attenuates-myocardial-oxidative-damage-via-promoting-autophagy-and-inhibiting-apoptosis
#6
Shujing Zhang, Ling Zhang, Han Zhang, Guanwei Fan, Jiuwen Qiu, Zongbao Fang, Haibo Wu, Yi Wang, Xiaoping Zhao
Natural products with antioxidative activities are widely applied to prevent and treat various oxidative stress related diseases, including ischemic heart disease. However, the cellular and molecular mechanisms of those therapies are still needed to be illustrated. In this study, we characterized the cardioprotective effects of Hongjingtian Injection (HJT), an extensively used botanical drug for treating coronary heart disease. The H/R-induced profound elevation of oxidative stress was suppressed by HJT. HJT also attenuates oxidative injury by promoting cell viability, intracellular ATP contents, and mitochondrial oxygen consumption...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28804534/mtor-inhibition-rejuvenates-the-aging-gingival-fibroblasts-through-alleviating-oxidative-stress
#7
Yiru Xia, Mengjun Sun, Yufeng Xie, Rong Shu
The aging periodontium may be vulnerable to periodontal pathogens and poor response to inflammation and susceptible to tumorigenesis. Human gingival fibroblasts (hGFs) through continuously replicative culture served as an in vitro surrogate for aging. To investigate the effects of the mechanistic target of rapamycin (mTOR) inhibition on the aging gingiva, we stimulated the high-passage hGFs with rapamycin (20 nmol/L) for 3 days and 30 days. The cellular and biological changes were examined by immunofluorescence, real-time PCR, ELISA, Western blotting, and flow cytometry...
2017: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/28803490/parkin-pink1-and-dj1-as-possible-modulators-of-mtor-pathway-in-ganglioglioma
#8
Katarzyna Drapalo, Jaroslaw Jozwiak
Ganglioglioma (GG) is a non-malignant tumor classified as G1 by the WHO. Although we currently know that the neoplasm may result from the hyperactivity of protein kinase B (PKB or Akt) or extracellular-regulated kinase (Erk), which upregulates mammalian target of rapamycin kinase (mTOR) and leads to translation of proteins responsible for cell cycle regulation, there are still many questions to be answered. In the current paper we try to analyze the link between GG formation and activity of three proteins known to play a role in neuroprotection...
August 14, 2017: International Journal of Neuroscience
https://www.readbyqxmd.com/read/28803361/toxoplasma-gondii-and-neospora-caninum-induce-different-host-cell-responses-at-proteome-wide-phosphorylation-events-a-step-forward-for-uncovering-the-biological-differences-between-these-closely-related-parasites
#9
Mariwan M M Al-Bajalan, Dong Xia, Stuart Armstrong, Nadine Randle, Jonathan M Wastling
Toxoplasma gondii and Neospora caninum are closely related intracellular protozoan parasites and tissue cyst-forming Coccidia of the phylum Apicomplexa. There are remarkable similarities between the morphology, genomes and transcriptomes of both parasites. Toxoplasma is zoonotic, with a wide host range and is mainly transmitted horizontally between its definitive host, the cat, and its intermediate hosts. Neospora causes disease within a narrow host range and with reduced virulence potential to the hosts. The dog is the definitive host of Neospora and its epidemiology in cattle mainly depends on vertical transmission...
August 12, 2017: Parasitology Research
https://www.readbyqxmd.com/read/28803046/design-synthesis-and-biological-evaluation-of-novel-pyrazolochalcones-as-potential-modulators-of-pi3k-akt-mtor-pathway-and-inducers-of-apoptosis-in-breast-cancer-cells
#10
Anver Basha Shaik, Garikapati Koteswara Rao, G Bharath Kumar, Nibeditha Patel, Vangala Santhosh Reddy, Irfan Khan, Sunitha Rani Routhu, C Ganesh Kumar, Immadi Veena, Kunta Chandra Shekar, Madan Barkume, Shailesh Jadhav, Aarti Juvekar, Jyoti Kode, Manika Pal-Bhadra, Ahmed Kamal
Cancer has been established as the "Emperor of all maladies". In recent years, medicinal chemistry has focused on identifying novel anti-cancer compounds; though discovery of these compounds appears to be a herculean task. In present study, we synthesized forty pyrazolochalcone conjugates and explored their cytotoxic activity against a panel of sixty cancer cell lines. Fifteen conjugates of the series showed excellent growth inhibition (13b-e, 13h-j, 14c-d, 15 a, 15 c-d, 16b, 16d and 18f; GI50 for MCF-7: 0...
July 25, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28802917/aerobic-exercise-in-adolescence-results-in-an-increase-of-neuronal-and-non-neuronal-cells-and-in-mtor-overexpression-in-the-cerebral-cortex-of-rats
#11
Angélica Begatti Victorino, Fernando Tadeu Serra, Pâmella Pimentel Piñero, Alexandre Aparecido de Almeida, Glauber Menezes Lopim, Ivair Matias Junior, Helio Rubens Machado, Roberto Lent, Francisco Romero Cabral, Fernando Gomez-Pinilla, Ricardo Mario Arida, Sérgio Gomes da Silva
Better cognitive performance and greater cortical and hippocampal volume have been observed in individuals who undertook aerobic exercise during childhood and adolescence. One possible explanation for these beneficial effects is that juvenile physical exercise enables better neural development and hence more cells and neuronal circuitries. It is probable that such effects occur through intracellular signaling proteins associated with cell growth, proliferation and survival. Based on this information, we evaluated the number of neuronal and non-neuronal cells using isotropic fractionation and the expression and activation of intracellular proteins (ERK, CREB Akt, mTOR and p70S6K) in the cerebral cortex and hippocampal formation of the rats submitted to a physical exercise program on a treadmill during adolescence...
August 9, 2017: Neuroscience
https://www.readbyqxmd.com/read/28802652/an-autophagic-mechanism-is-involved-in-the-6-hydroxydopamine-induced-neurotoxicity-in-vivo
#12
Xin He, Wei Yuan, Zijian Li, Juan Feng
6-hydroxydopamine (6-OHDA) is one of the most common agents for modeling dopaminergic neuron degeneration in Parkinson's disease (PD). So far, the role of autophagy in 6-OHDA-induced neurotoxicity remains controversial and most evidence is collected from in vitro studies. In this study, we determined the role of autophagy activation in 6-OHDA-induced neurotoxicity in a rat model of PD. Following 6-OHDA treatment, we observed a concomitant activation of autophagy and apoptosis. To further explore the interaction between autophagy and apoptosis induced by 6-OHDA, autophagy inhibitor 3-methylademine (3-MA) or cysteine protease inhibitor Z-FA-fmk was applied...
August 9, 2017: Toxicology Letters
https://www.readbyqxmd.com/read/28802586/nontypeable-haemophilus-influenzae-nthi-directly-interfere-with-the-regulation-of-e-cadherin-in-lung-epithelial-cells
#13
Inga Kaufhold, Sünja Osbahr, Kensuke Shima, Sebastian Marwitz, Kristina Rohmann, Daniel Drömann, Torsten Goldmann, Klaus Dalhoff, Jan Rupp
Loss of epithelial barriers characterized by reduction of E-cadherin is a hallmark of chronic obstructive pulmonary disease (COPD). We investigated the effects of nontypeable Haemophilus influenzae (NTHi) infections, associated with acute exacerbations of chronic bronchitis, on the regulation of E-cadherin in host cells. NTHi infection decreased E-cadherin mRNA and protein-levels in lung epithelial cells. E-cadherin reduction was mediated by activation of the fibroblast growth factor 2 (FGF2), the mammalian target of rapamycin (mTOR) and Slug...
August 10, 2017: Microbes and Infection
https://www.readbyqxmd.com/read/28802252/exploiting-radiation-induced-signaling-to-increase-the-susceptibility-of-resistant-cancer-cells-to-targeted-drugs-akt-and-mtor-inhibitors-as-an-example
#14
Iris Eke, Adeola Y Makinde, Molykutty J Aryankalayil, Veit Sandfort, Sanjeewani T Palayoor, Barbara H Rath, Lance Liotta, Mariaelena Pierobon, Emanuel F Petricoin, Matthew F Brown, Jayne M Stommel, Mansoor M Ahmed, C Norman Coleman
Implementing targeted drug therapy in radio-oncologic treatment regimens has greatly improved the outcome of cancer patients. However, the efficacy of molecular targeted drugs such as inhibitory antibodies or small molecule inhibitors essentially depends on target expression and activity, which both can change during the course of treatment. Radiotherapy has previously been shown to activate pro-survival pathways which can help tumor cells to adapt and thereby survive treatment. Therefore, we aimed to identify changes in signaling induced by radiation and evaluate the potential of targeting these changes with small molecules to increase the therapeutic efficacy on cancer cell survival...
August 11, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28802038/trem2-maintains-microglial-metabolic-fitness-in-alzheimer-s-disease
#15
Tyler K Ulland, Wilbur M Song, Stanley Ching-Cheng Huang, Jason D Ulrich, Alexey Sergushichev, Wandy L Beatty, Alexander A Loboda, Yingyue Zhou, Nigel J Cairns, Amal Kambal, Ekaterina Loginicheva, Susan Gilfillan, Marina Cella, Herbert W Virgin, Emil R Unanue, Yaming Wang, Maxim N Artyomov, David M Holtzman, Marco Colonna
Elevated risk of developing Alzheimer's disease (AD) is associated with hypomorphic variants of TREM2, a surface receptor required for microglial responses to neurodegeneration, including proliferation, survival, clustering, and phagocytosis. How TREM2 promotes such diverse responses is unknown. Here, we find that microglia in AD patients carrying TREM2 risk variants and TREM2-deficient mice with AD-like pathology have abundant autophagic vesicles, as do TREM2-deficient macrophages under growth-factor limitation or endoplasmic reticulum (ER) stress...
August 10, 2017: Cell
https://www.readbyqxmd.com/read/28801921/autophagy-impairment-by-caspase-1-dependent-inflammation-mediates-memory-loss-in-response-to-%C3%AE-amyloid-peptide-accumulation
#16
Lourdes Álvarez-Arellano, Martha Pedraza-Escalona, Tonali Blanco-Ayala, Nohemí Camacho-Concha, Javier Cortés-Mendoza, Leonor Pérez-Martínez, Gustavo Pedraza-Alva
β-Amyloid peptide accumulation in the cortex and in the hippocampus results in neurodegeneration and memory loss. Recently, it became evident that the inflammatory response triggered by β-Amyloid peptides promotes neuronal cell death and degeneration. In addition to inflammation, β-Amyloid peptides also induce alterations in neuronal autophagy, eventually leading to neuronal cell death. Thus, here we evaluated whether the inflammatory response induced by the β-Amyloid peptides impairs memory via disrupting the autophagic flux...
August 12, 2017: Journal of Neuroscience Research
https://www.readbyqxmd.com/read/28801734/fibrinogen-promotes-malignant-biological-tumor-behavior-involving-epithelial-mesenchymal-transition-via-the-p-akt-p-mtor-pathway-in-esophageal-squamous-cell-carcinoma
#17
Fei Zhang, Yun Wang, Peng Sun, Zhi-Qiang Wang, De-Shen Wang, Dong-Sheng Zhang, Feng-Hua Wang, Jian-Hua Fu, Rui-Hua Xu, Yu-Hong Li
PURPOSE: Hyperfibrinogenemia is associated with unfavorable prognosis and advanced tumor behavior in various malignancies, including esophageal squamous cell carcinoma (ESCC). However, its biological function in ESCC is unknown. The present study was designed to further validate the prognostic value of preoperative plasma hyperfibrinogenemia and evaluate the biological role of fibrinogen, as well as the underlying mechanism in ESCC. METHODS: Data from 452 cases with newly diagnosed ESCC followed by curative surgery between 2006 and 2010 were retrospectively evaluated...
August 11, 2017: Journal of Cancer Research and Clinical Oncology
https://www.readbyqxmd.com/read/28801605/luteolin-a-natural-flavonoid-inhibits-methylglyoxal-induced-apoptosis-via-the-mtor-4e-bp1-signaling-pathway
#18
Yi Liu, Jie Huang, Xian Zheng, Xia Yang, Yan Ding, Tongyong Fang, Yuyun Zhang, Shuaishuai Wang, Xiaofei Zhang, Xuan Luo, Anlei Guo, Kelly A Newell, Yinghua Yu, Xu-Feng Huang
Methylglyoxal (MG) accumulation has been observed in human cerebrospinal fluid and body tissues under hyperglycaemic conditions. Recent research has demonstrated that MG-induces neuronal cell apoptosis, which promotes the development of diabetic encephalopathy. Our previous animal study has shown that luteolin, a natural flavonoid, attenuates diabetes-associated cognitive dysfunction. To further explore the neuroprotective properties of luteolin, we investigated the inhibitive effect of luteolin on MG-induced apoptosis in PC12 neuronal cells...
August 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28801576/disrupting-glutamine-metabolic-pathways-to-sensitize-gemcitabine-resistant-pancreatic-cancer
#19
Ru Chen, Lisa A Lai, Yumi Sullivan, Melissa Wong, Lei Wang, Jonah Riddell, Linda Jung, Venu G Pillarisetty, Teresa A Brentnall, Sheng Pan
Pancreatic cancer is a lethal disease with poor prognosis. Gemcitabine has been the first line systemic treatment for pancreatic cancer. However, the rapid development of drug resistance has been a major hurdle in gemcitabine therapy leading to unsatisfactory patient outcomes. With the recent renewed understanding of glutamine metabolism involvement in drug resistance and immuno-response, we investigated the anti-tumor effect of a glutamine analog (6-diazo-5-oxo-L-norleucine) as an adjuvant treatment to sensitize chemoresistant pancreatic cancer cells...
August 11, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28800931/molecular-signatures-of-longevity-insights-from-cross-species-comparative-studies
#20
REVIEW
Siming Ma, Vadim N Gladyshev
Much of the current research on longevity focuses on the aging process within a single species. Several molecular players (e.g. IGF1 and MTOR), pharmacological compounds (e.g. rapamycin and metformin), and dietary approaches (e.g. calorie restriction and methionine restriction) have been shown to be important in regulating and modestly extending lifespan in model organisms. On the other hand, natural lifespan varies much more significantly across species. Within mammals alone, maximum lifespan differs more than 100 fold, but the underlying regulatory mechanisms remain poorly understood...
August 8, 2017: Seminars in Cell & Developmental Biology
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