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https://www.readbyqxmd.com/read/29660598/first-in-human-phase-1-dose-escalation-pharmacokinetic-and-pharmacodynamic-study-of-the-oral-dual-pi3k-and-mtorc1-2-inhibitor-pqr309-in-patients-with-advanced-solid-tumors-sakk-67-13
#1
Andreas Wicki, Nicholas Brown, Alexandros Xyrafas, Vincent Bize, Hanne Hawle, Simona Berardi, Nataša Cmiljanović, Vladimir Cmiljanović, Michael Stumm, Saša Dimitrijević, Richard Herrmann, Vincent Prêtre, Reto Ritschard, Alexandar Tzankov, Viviane Hess, Alexa Childs, Cinta Hierro, Jordi Rodon, Dagmar Hess, Markus Joerger, Roger von Moos, Cristiana Sessa, Rebecca Kristeleit
BACKGROUND: PQR309 is an orally bioavailable, balanced pan-phosphatidylinositol-3-kinase (PI3K), mammalian target of rapamycin (mTOR) C1 and mTORC2 inhibitor. PATIENTS AND METHODS: This is an accelerated titration, 3 + 3 dose-escalation, open-label phase I trial of continuous once-daily (OD) PQR309 administration to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics in patients with advanced solid tumours. Primary objectives were to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D)...
April 13, 2018: European Journal of Cancer
https://www.readbyqxmd.com/read/29660335/mtor-up-regulation-of-bex4-promotes-lung-adenocarcinoma-cell-proliferation-by-potentiating-oct4
#2
Ziran Zhao, Jiagen Li, Fengwei Tan, Shugeng Gao, Jie He
Previously, BEX family members have been reported to participate in cancer development. However, little is known about the role of BEX4 in lung adenocarcinoma (LAC). Here, we found that BEX4 was over-expressed in LAC tissues compared with adjacent tissues. LAC tissues from metastatic patients exhibited higher expression of BEX4 comparing to those from non-metastatic ones. In vitro, BEX4 ectopic expression accelerated the proliferation of both A549 and H1975 cells. By contrast, knockdown of BEX4 suppressed the proliferation of A549 and H1975 cells...
April 13, 2018: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/29655655/hypothalamic-peroxisome-proliferator-activated-receptor-gamma-regulates-ghrelin-production-and-food-intake
#3
Qingjie Li, Quan Yu, Li Lin, Heng Zhang, Miao Peng, Chunxia Jing, Geyang Xu
Peroxisome proliferator-activated receptor-γ (PPARγ) regulates fatty acid storage, glucose metabolism, and food intake. Ghrelin, a gastric hormone, provides a hunger signal to the central nervous system to stimulate appetite. However, the effects of PPARγ on ghrelin production are still unclear. In the present study, the effects of PPARγ on ghrelin production were examined in lean- or high-fat diet-induced obese (DIO) C57BL/6J mice and mHypoE-42 cells, a hypothalamic cell line. 3rd intracerebroventricular injection of adenoviral-directed overexpression of PPARγ (Ad-PPARγ) reduced hypothalamic and plasma ghrelin, food intake in both lean C57BL/6J mice and diet-induced obese mice...
April 9, 2018: Neuropeptides
https://www.readbyqxmd.com/read/29651002/metformin-decreases-the-incidence-of-pancreatic-ductal-adenocarcinoma-promoted-by-diet-induced-obesity-in-the-conditional-krasg12d-mouse-model
#4
Hui-Hua Chang, Aune Moro, Caroline Ei Ne Chou, David W Dawson, Samuel French, Andrea I Schmidt, James Sinnett-Smith, Fang Hao, O Joe Hines, Guido Eibl, Enrique Rozengurt
Pancreatic ductal adenocarcinoma (PDAC) is a particularly deadly disease. Chronic conditions, including obesity and type-2 diabetes are risk factors, thus making PDAC amenable to preventive strategies. We aimed to characterize the chemo-preventive effects of metformin, a widely used anti-diabetic drug, on PDAC development using the KrasG12D mouse model subjected to a diet high in fats and calories (HFCD). LSL-KrasG12D/+ ;p48-Cre (KC) mice were given control diet (CD), HFCD, or HFCD with 5 mg/ml metformin in drinking water for 3 or 9 months...
April 12, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29644770/tmem55b-contributes-to-lysosomal-homeostasis-and-amino-acid-induced-mtorc1-activation
#5
Yutaka Hashimoto, Michiko Shirane, Keiichi I Nakayama
Mammalian/mechanistic target of rapamycin complex 1 (mTORC1) responds to growth factors and nutrient availability. Amino acids induce the recruitment of mTORC1 to the lysosomal membrane and its consequent activation, but the molecular mechanism of such activation has remained unclear. We have now examined the role of TMEM55B, a lysosomal protein of unknown molecular function, in this process on the basis of the results of proteomics and immunofluorescence analyses showing that TMEM55B interacts with many proteins that participate in mTORC1 activation including components of the vacuolar-type proton ATPase (V-ATPase) and Ragulator complexes at the lysosomal membrane...
April 11, 2018: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
https://www.readbyqxmd.com/read/29628303/overexpression-of-tfeb-drives-a-pleiotropic-neurotrophic-effect-and-prevents-parkinson-s-disease-related-neurodegeneration
#6
Albert Torra, Annabelle Parent, Thais Cuadros, Beatriz Rodríguez-Galván, Esther Ruiz-Bronchal, Andrea Ballabio, Analía Bortolozzi, Miquel Vila, Jordi Bové
The possible implication of transcription factor EB (TFEB) as a therapeutic target in Parkinson's disease has gained momentum since it was discovered that TFEB controls lysosomal biogenesis and autophagy and that its activation might counteract lysosomal impairment and protein aggregation. However, the majority of putative direct targets of TFEB described to date is linked to a range of biological processes that are not related to the lysosomal-autophagic system. Here, we assessed the effect of overexpressing TFEB with an adeno-associated viral vector in mouse substantia nigra dopaminergic neurons...
February 27, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29626653/neuronal-lysosomes
#7
REVIEW
Shawn M Ferguson
Lysosomes support diverse cellular functions by acting as sites of macromolecule degradation and nutrient recycling. The degradative abilities of lysosomes are conferred by a lumen that is characterized by an acidic pH and which contains numerous hydrolases that support the breakdown of major cellular macromolecules to yield cellular building blocks (amino acids, nucleic acids, sugars, lipids and metals) that are transported into the cytoplasm for their re-use. In addition to these important hydrolytic and recycling functions, lysosomes also serve as a signaling platform that integrates nutrient and metabolic cues to control signaling via the mTORC1 pathway...
April 4, 2018: Neuroscience Letters
https://www.readbyqxmd.com/read/29625038/finding-sugar-in-the-pantry-how-galectins-detect-and-signal-lysosomal-damage
#8
Hijai R Shin, Roberto Zoncu
In this issue of Molecular Cell, Jia et al. (2018) identify a lysosomal damage-response pathway centered on galectin 8 and 9 that feeds back on mTORC1 signaling. In response to lysosome-damaging agents, galectins inhibits mTORC1, triggering a stress response that may help restore cellular homeostasis.
April 5, 2018: Molecular Cell
https://www.readbyqxmd.com/read/29623577/use-of-dual-mtor-inhibitor-mln0128-against-everolimus-resistant-breast-cancer
#9
Karineh Petrossian, Duc Nguyen, Chiao Lo, Noriko Kanaya, George Somlo, Yvonne Xiaoyong Cui, Chiun-Sheng Huang, Shiuan Chen
PURPOSE: HR+/HER2- aromatase inhibitor-resistant metastatic breast cancer can be treated with everolimus and a second AI until the cancer recurs. Targeting these everolimus-resistant patients with the latest standard of care, CDK4/6 inhibitors, has not been clearly addressed. Understanding the signaling transduction pathways, which everolimus resistance activates, will elucidate the mechanisms and offer treatment strategies of everolimus resistance. METHODS: To mimic the clinical setting, letrozole-resistant cells were used to generate an everolimus-resistant model (RAD-R)...
April 5, 2018: Breast Cancer Research and Treatment
https://www.readbyqxmd.com/read/29622767/pex5-regulates-autophagy-via-the-mtorc1-tfeb-axis-during-starvation
#10
So Young Eun, Joon No Lee, In-Koo Nam, Zhi-Qiang Liu, Hong-Seob So, Seong-Kyu Choe, RaeKil Park
Defects in the PEX5 gene impair the import of peroxisomal matrix proteins, leading to nonfunctional peroxisomes and other associated pathological defects such as Zellweger syndrome. Although PEX5 regulates autophagy process in a stress condition, the mechanisms controlling autophagy by PEX5 under nutrient deprivation are largely unknown. Herein, we show a novel function of PEX5 in the regulation of autophagy via Transcription Factor EB (TFEB). Under serum-starved conditions, when PEX5 is depleted, the mammalian target of rapamycin (mTORC1) inhibitor TSC2 is downregulated, which results in increased phosphorylation of the mTORC1 substrates, including 70S6K, S6K, and 4E-BP-1...
April 6, 2018: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29622588/modeling-the-transition-from-decompensated-to-pathological-hypertrophy
#11
Florencia Pascual, Jonathan C Schisler, Trisha J Grevengoed, Monte S Willis, Rosalind A Coleman
BACKGROUND: Long-chain acyl-CoA synthetases (ACSL) catalyze the conversion of long-chain fatty acids to fatty acyl-CoAs. Cardiac-specific ACSL1 temporal knockout at 2 months results in a shift from FA oxidation toward glycolysis that promotes mTORC1-mediated ventricular hypertrophy. We used unbiased metabolomics and gene expression analyses to examine the early effects of genetic inactivation of fatty acid oxidation on cardiac metabolism, hypertrophy development, and function. METHODS AND RESULTS: Global cardiac transcriptional analysis revealed differential expression of genes involved in cardiac metabolism, fibrosis, and hypertrophy development in Acsl1 H-/- hearts 2 weeks after Acsl1 ablation...
April 5, 2018: Journal of the American Heart Association
https://www.readbyqxmd.com/read/29621758/targeting-mtor-by-cz415-inhibits-head-and-neck-squamous-cell-carcinoma-cells
#12
Jing Xie, Quan Li, Xi Ding, Yunyun Gao
BACKGROUND/AIMS: mTOR is an important therapeutic target for human head and neck squamous cell carcinoma (HNSCC). The current study tested the anti-HNSCC cell activity by a mTOR kinase inhibitor CZ415. METHODS: HNSCC cells were treated with CZ415. Cell death was tested by lactate dehydrogenase (LDH) assay and MTT assay. Cell proliferation was tested by BrdU ELISA assay and [H3] thymidine incorporation assay, with apoptosis assayed by the TUNEL staining. A Western blotting assay was applied to test autophagy-associated proteins, mTOR and signalings...
March 29, 2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29621478/hyperglycemia-induced-bcl-2-bax-mediated-apoptosis-of-schwann-cells-via-mtorc1-s6k1-inhibition-in-diabetic-peripheral-neuropathy
#13
Lin Zhu, Jun Hao, Meijuan Cheng, Cuihong Zhang, Chunxiu Huo, Yaping Liu, Wei Du, Xianghong Zhang
Schwann cell apoptosis is one of the characteristics of diabetic peripheral neuropathy (DPN). The mammalian target of rapamycin (mTOR) is a multifunctional signaling pathway that regulates cell apoptosis in various types of tissues and cells. To investigate whether the mTOR pathway is involved in cell apoptosis in the Schwann cells of DPN, diabetic mice and rat Schwann cells (RSC96) were chosen to detect phospho-mTOR (Ser 2448), phospho-S6K1 (Thr 389), phospho-4EBP1 (Thr 37/46), Bcl-2, Bax and cleaved caspase-3 by diverse pathological and biological techniques...
April 2, 2018: Experimental Cell Research
https://www.readbyqxmd.com/read/29618633/seh1-targets-gator2-and-nup153-to-mitotic-chromosomes
#14
Melpomeni Platani, Itaru Samejima, Kumiko Samejima, Masato T Kanemaki, W C Earnshaw
In metazoa the Nup107-160 nucleoporin Y complex plays a major role in formation of the nuclear pore complex in interphase and is localised to kinetochores in mitosis. The Nup107-160 complex shares a single highly conserved subunit, Seh1, with the GATOR2 complex, an essential activator of mTORC1 kinase. mTORC1/GATOR2 has a central role in the coordination of cell growth and proliferation. Here we use chemical genetics and quantitative chromosome proteomics to study the role of the Seh1 protein in mitosis. Surprisingly, Seh1 is not required for the association of the Nup107-160 complex with mitotic chromosomes, but it is essential for the association of both GATOR2 complex and nucleoporin Nup153 with mitotic chromosomes...
April 3, 2018: Journal of Cell Science
https://www.readbyqxmd.com/read/29617677/the-mtor-kinase-inhibitor-cz415-inhibits-human-papillary-thyroid-carcinoma-cell-growth
#15
Xiaobin Li, Zongze Li, Yimin Song, Wenjing Liu, Ziwen Liu
BACKGROUND/AIM: Mammalian target of rapamycin (mTOR) plays an important role in papillary thyroid carcinoma (PTC) cell progression. CZ415 is a novel, highly-efficient and specific mTOR kinase inhibitor. The current study tested the potential anti-tumor activity of CZ415 in human PTC cells. METHODS: The established (TPC-1 cell line) and primary human PTC cells were treated with CZ415. Cell survival and growth were tested by Cell Counting Kit-8 assay and BrdU ELISA assay, respectively...
March 28, 2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29614494/deptor-deficiency-mediated-mtorc1-hyperactivation-in-vascular-endothelial-cells-promotes-angiogenesis
#16
Yan Ding, Lanlan Shan, Wenqing Nai, Xiaojun Lin, Ling Zhou, Xiaoying Dong, Hongyuan Wu, Min Xiao, Xuejuan Zhou, Linlin Wang, Ting Li, You Fu, Yijun Lin, Chunhong Jia, Meng Dai, Xiaochun Bai
BACKGROUND/AIMS: The mechanistic target of rapamycin (mTOR) signaling pathway is essential for angiogenesis and embryonic development. DEP domain-containing mTOR-interacting protein (DEPTOR) is an mTOR binding protein that functions to inhibit the mTOR pathway In vitro experiments suggest that DEPTOR is crucial for vascular endothelial cell (EC) activation and angiogenic responses. However, knowledge of the effects of DEPTOR on angiogenesis in vivo is limited. This study aimed to determine the role of DEPTOR in tissue angiogenesis and to elucidate the molecular mechanisms...
March 26, 2018: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29611762/-guaiol-regulates-autophagic-cell-death-depending-on-mtor-signaling-in-nsclc
#17
Xiaohui Yang, Jiabei Zhu, Jianchun Wu, Nan Huang, Zhongqi Cui, Yingbin Luo, Fenyong Sun, Qiuhui Pan, Yan Li, Qingyuan Yang
(-)-Guaiol, a sesquiterpene alcohol with the guaiane skeleton, has been found in many Chinese medicinal plants and been reported to comprise various guaiane natural products that are well known for their antibacterial activities. Previously, we have shown its antitumor activity by inducing autophagy in NSCLC cells. However, its potential mechanism in inducing autophagy is still under our investigation. Here, data from our western blotting assays showed that, in NSCLC cells, (-)-Guaiol significantly blocked the mTORC2-AKT signaling by suppressing mTOR phosphorylation at serine 2481 (S2481) to induce autophagy, illustrated by the increasing ratio of LC3II/I...
April 3, 2018: Cancer Biology & Therapy
https://www.readbyqxmd.com/read/29608149/a-rankl-based-osteoclast-culture-assay-of-mouse-bone-marrow-to-investigate-the-role-of-mtorc1-in-osteoclast-formation
#18
Qinggang Dai, Yujiao Han, Furong Xie, Xuhui Ma, Zhan Xu, Xiao Liu, Weiguo Zou, Jun Wang
Osteoclasts are unique bone-resorbing cells that differentiate from the monocyte/macrophage lineage of bone marrow. Dysfunction of osteoclasts may result in a series of bone metabolic diseases, including osteoporosis. To develop pharmaceutical targets for the prevention of pathological bone mass loss, the mechanisms by which osteoclasts differentiate from precursors must be understood. The ability to isolate and culture a large number of osteoclasts in vitro is critical in order to determine the role of specific genes in osteoclast differentiation...
March 15, 2018: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/29607465/sirolimus-enhances-remission-induction-in-patients-with-high-risk-acute-myeloid-leukemia-and-mtorc1-target-inhibition
#19
Margaret T Kasner, Rosemarie Mick, Grace R Jeschke, Matthew Carabasi, Joanne Filicko-O'Hara, Neal Flomenberg, Noelle V Frey, Elizabeth O Hexner, Selina M Luger, Alison W Loren, James K Mangan, John L Wagner, Mark Weiss, Martin Carroll, Alexander E Perl
Background Mammalian Target of Rapamycin Complex 1 (mTORC1) inhibitors enhance chemotherapy response in acute myelogenous leukemia (AML) cells in vitro. However whether inhibiting mTORC1 enhances clinical response to AML chemotherapy remains controversial. We previously optimized measurement of mTORC1's kinase activity in AML blasts during clinical trials using serial phospho-specific flow cytometry of formaldehyde-fixed whole blood or marrow specimens. To validate mTORC1 as a therapeutic target in AML, we performed two clinical trials combining an mTORC1 inhibitor (sirolimus) and MEC (mitoxantrone, etoposide, cytarabine) in patients with relapsed, refractory, or untreated high-risk AML...
April 2, 2018: Investigational New Drugs
https://www.readbyqxmd.com/read/29596905/rapamycin-modulates-glucocorticoid-receptor-function-blocks-atrophogene-redd1-and-protects-skin-from-steroid-atrophy
#20
Ekaterina Lesovaya, Shivani Agarwal, Ben Readhead, Elena Vinokour, Gleb Baida, Pankaj Bhalla, Kirill Kirsanov, Marianna Yakubovskaya, Leonidas C Platanias, Joel T Dudley, Irina Budunova
Glucocorticoids have excellent therapeutic properties; however, they cause significant adverse atrophogenic effects. mTOR complex 1 (mTORC1) inhibitor, REDD1 (regulated in development and DNA damage 1), has been recently identified as a key mediator of glucocorticoid-induced atrophy. We performed computational screening of connectivity map database (CMAP) to identify putative REDD1 inhibitors. The top selected candidates included Rapamycin, which was unexpected because it inhibits pro-proliferative mTOR signaling...
March 26, 2018: Journal of Investigative Dermatology
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