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target of rapamycin

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https://www.readbyqxmd.com/read/29145153/the-pro-apoptosis-effect-of-sinomenine-in-renal-carcinoma-via-inducing-autophagy-through-inactivating-pi3k-akt-mtor-pathway
#1
Fei Deng, Yue-Xian Ma, Liang Liang, Ping Zhang, Jing Feng
Renal cell carcinoma (RCC) is a heterogeneous histological disease and the most common kidney cancer. The mortality rate of RCC remains high despite the improved treatment. Sinomenine is an isoquinoline extracted from Chinese medicinal plant Sinomenium acutum, famous for its ability to suppress several cancer cell types. Our research aimed to explore the anti-cancer potential of sinomenine in RCC. Results showed that sinomenine reduced the viability by reducing sphere-forming ability and enhancing pro-apoptosis effect in ACHN cells in a dose dependent manner...
November 13, 2017: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/29144835/modern-systemic-therapy-for-metastatic-renal-cell-carcinoma-of-the-clear-cell-type
#2
Mamta Parikh, Primo N Lara
In the last 30 years, there have been many advances in the treatment of metastatic renal cell carcinoma of the clear cell type. Renal cell carcinoma has long been understood to have a component of immune mediation and has been responsive to immune-based therapies; in addition to early cytokine therapy, newer checkpoint inhibition therapies have also demonstrated activity. Molecular characterization of the genome of clear cell renal cell carcinoma enabled identification of the roles of angiogenesis and hypoxic stress...
November 16, 2017: Annual Review of Medicine
https://www.readbyqxmd.com/read/29144820/pheochromocytoma-a-genetic-and-diagnostic-update
#3
Leilani B Mercado-Asis, Katherine I Wolf, Ivana Jochmanova, David Taïeb
OBJECTIVE: Pheochromocytomas and paragangliomas (PPGLs) are neuroendocrine tumors derived from adrenal or extra-adrenal locations, respectively. Upon suspicion of PPGL, specific metabolomic, molecular, biochemical, imaging, and histopathological studies are performed to prove, localize, treat, and monitor disease progression. Recently, improved diagnostic tools allow physicians to accurately diagnose PPGL, even in patients presenting with small (less than 1 cm) or biochemically silent tumors, which previously delayed proper detection and treatment...
November 16, 2017: Endocrine Practice
https://www.readbyqxmd.com/read/29143563/mammalian-target-of-rapamycin-complex-2-mtorc2-controls-glycolytic-gene-expression-by-regulating-histone-h3-lysine-56-acetylation
#4
Raghavendra Vadla, Devyani Haldar
Metabolic reprogramming is a hallmark of cancer cells, but the mechanisms are not well understood. The mammalian target of rapamycin complex 2 (mTORC2) controls cell growth and proliferation and plays a critical role in metabolic reprogramming in glioma. mTORC2 regulates cellular processes such as cell survival, metabolism, and proliferation by phosphorylation of AGC kinases. Components of mTORC2 are shown to localize to the nucleus, but whether mTORC2 modulates epigenetic modifications to regulate gene expression is not known...
November 16, 2017: Cell Cycle
https://www.readbyqxmd.com/read/29143288/gsk3%C3%AE-controls-mtor-and-prosurvival-signaling-in-neurons
#5
Malgorzata Urbanska, Agata Gozdz, Matylda Macias, Iwona A Cymerman, Ewa Liszewska, Ilona Kondratiuk, Herman Devijver, Benoit Lechat, Fred Van Leuven, Jacek Jaworski
Glycogen synthase kinases-3β (GSK3β) is a key regulator of cell homeostasis. In neurons, GSK3β contributes to control of neuronal transmission and plasticity. Despite extensive studies in non-neuronal cells, crosstalk between GSK3β and other signaling pathways remains not well defined in neurons. In the present study, we report that GSK3β positively affected the activity of effectors of mammalian target of rapamycin complex 1 (mTORC1) and complex 2 (mTORC2), in mature neurons in vitro and in vivo. GSK3β also promoted prosurvival signaling and attenuated kainic acid-induced apoptosis...
November 15, 2017: Molecular Neurobiology
https://www.readbyqxmd.com/read/29138868/hdac-inhibitor-lmk%C3%A2-235-promotes-the-odontoblast-differentiation-of-dental-pulp-cells
#6
Zhao Liu, Ting Chen, Qianqian Han, Ming Chen, Jie You, Fuchun Fang, Ling Peng, Buling Wu
The role of dental pulp cells (DPCs) in hard dental tissue regeneration had received increasing attention because DPCs can differentiate into odontoblasts and other tissue‑specific cells. In recent years, epigenetic modifications had been identified to serve an important role in cell differentiation, and histone deacetylase (HDAC) inhibitors have been widely studied by many researchers. However, the effects of HDAC4 and HDAC5 on the differentiation of DPCs and the precise molecular mechanisms remain unclear...
November 14, 2017: Molecular Medicine Reports
https://www.readbyqxmd.com/read/29138277/coupling-shrna-screens-with-single-cell-rna-seq-identifies-a-dual-role-for-mtor-in-reprogramming-induced-senescence
#7
Marieke Aarts, Athena Georgilis, Meryam Beniazza, Patrizia Beolchi, Ana Banito, Thomas Carroll, Marizela Kulisic, Daniel F Kaemena, Gopuraja Dharmalingam, Nadine Martin, Wolf Reik, Johannes Zuber, Keisuke Kaji, Tamir Chandra, Jesús Gil
Expression of the transcription factors OCT4, SOX2, KLF4, and cMYC (OSKM) reprograms somatic cells into induced pluripotent stem cells (iPSCs). Reprogramming is a slow and inefficient process, suggesting the presence of safeguarding mechanisms that counteract cell fate conversion. One such mechanism is senescence. To identify modulators of reprogramming-induced senescence, we performed a genome-wide shRNA screen in primary human fibroblasts expressing OSKM. In the screen, we identified novel mediators of OSKM-induced senescence and validated previously implicated genes such as CDKN1A We developed an innovative approach that integrates single-cell RNA sequencing (scRNA-seq) with the shRNA screen to investigate the mechanism of action of the identified candidates...
November 14, 2017: Genes & Development
https://www.readbyqxmd.com/read/29137436/tumor-biopsy-stratification-based-on-mtor-pathway-activity-and-functional-mutations-in-the-upstream-genes-pik3ca-and-pten
#8
Jean-François Laes, Sebastien Sauvage, Gregori Ghitti
The mechanistic target of the rapamycin (mTOR) pathway is frequently activated in human cancers. Our objective was to evaluate relationships between mTOR-pathway activity and functional mutations in the upstream genes PIK3CA and PTEN in solid-tumor biopsies from a broad selection of cancer types. Formalin-fixed paraffin-embedded (FFPE) tumor samples were analyzed by immunohistochemistry (IHC) and next-generation sequencing (NGS). TOR-pathway activation was identified by expression (by IHC) of the downstream effector p-4E-BP1...
October 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/29137365/longitudinal-serum-metabolomics-evaluation-of-trastuzumab-and-everolimus-combination-as-pre-operative-treatment-for-her-2-positive-breast-cancer-patients
#9
Elodie Jobard, Olivier Trédan, Thomas Bachelot, Arnaud M Vigneron, Céline Mahier Aït-Oukhatar, Monica Arnedos, Maria Rios, Jacques Bonneterre, Véronique Diéras, Marta Jimenez, Jean-Louis Merlin, Mario Campone, Bénédicte Elena-Herrmann
The mammalian target of rapamycin complex 1 (mTORC1) is an attractive target for HER-2 positive breast cancer therapy because of its key role in protein translation regulation, cell growth and metabolism. We present here a metabolomic investigation exploring the impact of mTOR inhibition on serum metabolic profiles from patients with non-metastatic breast cancer overexpressing HER-2. Baseline, treatment-related and post-treatment serum samples were analyzed for 79 patients participating in the French clinical trial RADHER, in which randomized patients with HER-2 positive breast cancer received either trastuzumab alone (arm T) or a trastuzumab and everolimus combination (arm T+E)...
October 13, 2017: Oncotarget
https://www.readbyqxmd.com/read/29136244/a-molecular-cascade-modulates-map1b-and-confers-resistance-to-mtor-inhibition-in-human-glioblastoma
#10
Dan R Laks, Juan A Oses-Prieto, Alvaro G Alvarado, Jonathan Nakashima, Shreya Chand, Daniel B Azzam, Ankur A Gholkar, Jantzen Sperry, Kirsten Ludwig, Michael C Condro, Serli Nazarian, Anjelica Cardenas, Michelle Y S Shih, Robert Damoiseaux, Bryan France, Nicholas Orozco, Koppany Visnyei, Thomas J Crisman, Fuying Gao, Jorge Z Torres, Giovanni Coppola, Alma L Burlingame, Harley I Kornblum
Background: Clinical trials of therapies directed against nodes of the PI3K/AKT/mTOR signaling axis in Glioblastoma (GBM) have had disappointing results. Resistance to mTOR inhibitors limits their efficacy. Methods: To determine mechanisms of resistance to chronic mTOR inhibition, we performed tandem screens on patient-derived GBM cultures. Results: An unbiased phosphoproteomic screen quantified phosphorylation changes associated with chronic exposure to the mTOR inhibitor rapamycin and our analysis implicated a role for GSK3B attenuation in mediating resistance that was confirmed by functional studies...
November 9, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/29134654/pten-loss-and-activation-of-k-ras-and-%C3%AE-catenin-cooperate-to-accelerate-prostate-tumourigenesis
#11
Matthew T Jefferies, Adam C Cox, Boris Y Shorning, Valerie Meniel, David Griffiths, Howard G Kynaston, Matthew J Smalley, Alan R Clarke
Aberrant phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK) and WNT signalling are emerging as key events in the multistep nature of prostate tumourigenesis and progression. Here, we report a compound prostate cancer murine model in which these signalling pathways cooperate to produce a more aggressive prostate cancer phenotype. Using Cre-LoxP technology and the probasin promoter, we combined the loss of Pten (Pten(fl/fl) ), to activate the PI3K signalling pathway, with either dominant stabilized β-catenin [Catnb(+/lox(ex3)) ] or activated K-RAS (K-Ras(+/V12) ) to aberrantly activate WNT and MAPK signalling, respectively...
November 14, 2017: Journal of Pathology
https://www.readbyqxmd.com/read/29133952/engaging-homeostatic-plasticity-to-treat-depression
#12
E R Workman, F Niere, K F Raab-Graham
Major depressive disorder (MDD) is a complex and heterogeneous mood disorder, making it difficult to develop a generalized, pharmacological therapy that is effective for all who suffer from MDD. Through the fortuitous discovery of N-methyl-D-aspartate receptor (NMDAR) antagonists as effective antidepressants, we have gained key insights into how antidepressant effects can be produced at the circuit and molecular levels. NMDAR antagonists act as rapid-acting antidepressants such that relief from depressive symptoms occurs within hours of a single injection...
November 14, 2017: Molecular Psychiatry
https://www.readbyqxmd.com/read/29133782/mtor-intersects-antibody-inducing-signals-from-taci-in-marginal-zone-b-cells
#13
Jordi Sintes, Maurizio Gentile, Shuling Zhang, Yolanda Garcia-Carmona, Giuliana Magri, Linda Cassis, Daniel Segura-Garzón, Alessandra Ciociola, Emilie K Grasset, Sabrina Bascones, Laura Comerma, Marc Pybus, David Lligé, Irene Puga, Cindy Gutzeit, Bing He, Wendy DuBois, Marta Crespo, Julio Pascual, Anna Mensa, Juan Ignacio Aróstegui, Manel Juan, Jordi Yagüe, Sergi Serrano, Josep Lloreta, Eric Meffre, Michael Hahne, Charlotte Cunningham-Rundles, Beverly A Mock, Andrea Cerutti
Mechanistic target of rapamycin (mTOR) enhances immunity in addition to orchestrating metabolism. Here we show that mTOR coordinates immunometabolic reconfiguration of marginal zone (MZ) B cells, a pre-activated lymphocyte subset that mounts antibody responses to T-cell-independent antigens through a Toll-like receptor (TLR)-amplified pathway involving transmembrane activator and CAML interactor (TACI). This receptor interacts with mTOR via the TLR adapter MyD88. The resulting mTOR activation instigates MZ B-cell proliferation, immunoglobulin G (IgG) class switching, and plasmablast differentiation through a rapamycin-sensitive pathway that integrates metabolic and antibody-inducing transcription programs, including NF-κB...
November 13, 2017: Nature Communications
https://www.readbyqxmd.com/read/29132870/mtor-inhibitor-rapamycin-induce-polymorphonuclear-myeloid-derived-suppressor-cells-mobilization-and-function-in-protecting-against-acute-graft-versus-host-disease-after-bone-marrow-transplantation
#14
Yu Lin, Binsheng Wang, Wei Shan, Yamin Tan, Jingjing Feng, Lin Xu, Limengmeng Wang, Biqing Han, Mingming Zhang, Jian Yu, Xiaohong Yu, He Huang
The mammalian target of rapamycin (mTOR) inhibitor rapamycin (RAPA) has been shown to be an effective immunosuppressor in the management of acute graft-versus-host disease (aGVHD) after bone marrow transplantation. Myeloid-derived suppressor cells (MDSCs) also have a protective effect in aGVHD regulation. However, the relationship between RAPA and MDSCs in aGVHD models is unclear. Meanwhile, the effect of RAPA on different subgroups of MDSCs is also less well described. In this study, we demonstrate that in vivo administration of RAPA results in the expansion and functional enhancement of polymorphonuclear MDSCs (PMN-MDSCs) in a murine model of aGVHD...
November 10, 2017: Clinical Immunology: the Official Journal of the Clinical Immunology Society
https://www.readbyqxmd.com/read/29130236/-occurrence-diagnosis-and-treatment-of-de-novo-gastrointestinal-malignancies-after-organ-transplantation
#15
Linhua Ji, Gang Zhao
With the continuous use of immunosuppressive agents routinely, the long-term survival rate of organ transplant recipients has been incessantly improved. However, the risk of de novo malignancies is also increasing, which has become the second cause of death after organ transplantation. De novo gastrointestinal malignancies are common after liver or kidney transplantation, mostly with advanced stage when diagnosed and poor prognosis. There is a significant trend in the development of de novo malignancies in transplant recipients, which is probably related to factors, including direct or indirect effects of immunosuppressive agents, precancerosis and survival time of transplanted grafts and recipients...
October 25, 2017: Zhonghua Wei Chang Wai Ke za Zhi, Chinese Journal of Gastrointestinal Surgery
https://www.readbyqxmd.com/read/29129088/systemic-therapy-for-esophagogastric-cancer-targeted-therapies
#16
Tomas G Lyons, Geoffrey Y Ku
The poor prognosis for patients with esophagogastric cancers (EGC) has resulted in an increased focus on the use of targeted agents in this disease. Targets include epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), Her2, mammalian target of rapamycin (mTOR), MET, poly (ADP-ribose) polymerase (PARP) and claudin 18.2 (CLDN18.2). Trastuzumab, an anti-Her2 antibody, was approved by the U.S. FDA in 2010 as first-line therapy in combination with chemotherapy for Her2-positive disease...
October 2017: Chinese Clinical Oncology
https://www.readbyqxmd.com/read/29127238/protective-effects-of-the-mechanistic-target-of-rapamycin-against-excess-iron-and-ferroptosis-in-cardiomyocytes
#17
Yuichi Baba, Jason K Higa, Briana K Shimada, Kate M Horiuchi, Tomohiro Suhara, Motoi Kobayashi, Jonathan D Woo, Hiroko Aoyagi, Karra S Marh, Hiroaki Kitaoka, Takashi Matsui
Clinical studies suggest that myocardial iron is a risk factor for left ventricular remodeling in patients after myocardial infarction (MI). Ferroptosis was recently reported as a mechanism of iron-dependent non-apoptotic cell death. However, ferroptosis in the heart is not well understood. The mechanistic target of rapamycin (mTOR) protects the heart against pathological stimuli such as ischemia. To define the role of cardiac mTOR on cell survival in iron-mediated cell death, we examined cardiomyocyte (CM) cell viability under excess iron and ferroptosis conditions...
November 10, 2017: American Journal of Physiology. Heart and Circulatory Physiology
https://www.readbyqxmd.com/read/29127204/mutations-in-the-x-linked-atp6ap2-cause-a-glycosylation-disorder-with-autophagic-defects
#18
Maria A Rujano, Magda Cannata Serio, Ganna Panasyuk, Romain Péanne, Janine Reunert, Daisy Rymen, Virginie Hauser, Julien H Park, Peter Freisinger, Erika Souche, Maria Clara Guida, Esther M Maier, Yoshinao Wada, Stefanie Jäger, Nevan J Krogan, Oliver Kretz, Susana Nobre, Paula Garcia, Dulce Quelhas, Thomas D Bird, Wendy H Raskind, Michael Schwake, Sandrine Duvet, Francois Foulquier, Gert Matthijs, Thorsten Marquardt, Matias Simons
The biogenesis of the multi-subunit vacuolar-type H(+)-ATPase (V-ATPase) is initiated in the endoplasmic reticulum with the assembly of the proton pore V0, which is controlled by a group of assembly factors. Here, we identify two hemizygous missense mutations in the extracellular domain of the accessory V-ATPase subunit ATP6AP2 (also known as the [pro]renin receptor) responsible for a glycosylation disorder with liver disease, immunodeficiency, cutis laxa, and psychomotor impairment. We show that ATP6AP2 deficiency in the mouse liver caused hypoglycosylation of serum proteins and autophagy defects...
November 10, 2017: Journal of Experimental Medicine
https://www.readbyqxmd.com/read/29124519/prognostic-and-predictive-role-of-the-pi3k-akt-mtor-pathway-in-neuroendocrine-neoplasms
#19
REVIEW
P Gajate, T Alonso-Gordoa, O Martínez-Sáez, J Molina-Cerrillo, E Grande
Neuroendocrine neoplasms (NENs) are considered a heterogeneous and rare entity. Its natural history is influenced by multiple clinicopathological characteristics, which guide the management of these patients. The development of molecular biology reveals that the PI3K-AKT-mTOR pathway plays a relevant role in tumorigenesis and progression of NENs. Mammalian target of rapamycin (mTOR) inhibitors, targeted agents that block this pathway, has improved outcomes in neuroendocrine tumors (NETs). Different therapeutic approaches, such as somatostatin analogs, chemotherapy, peptide receptor radionuclide therapy, and targeted agents, have shown benefits in the treatment of NETs...
November 9, 2017: Clinical & Translational Oncology
https://www.readbyqxmd.com/read/29123114/structural-basis-for-ragulator-functioning-as-a-scaffold-in-membrane-anchoring-of-rag-gtpases-and-mtorc1
#20
Tianlong Zhang, Rong Wang, Zhijing Wang, Xiangxiang Wang, Fang Wang, Jianping Ding
Amino acid-dependent activation of the mechanistic target of rapamycin complex 1 (mTORC1) is mediated by Rag GTPases, which are recruited to the lysosome by the Ragulator complex consisting of p18, MP1, p14, HBXIP and C7orf59; however, the molecular mechanism is elusive. Here, we report the crystal structure of Ragulator, in which p18 wraps around the MP1-p14 and C7orf59-HBXIP heterodimers and the interactions of p18 with MP1, C7orf59, and HBXIP are essential for the assembly of Ragulator. There are two binding sites for the Roadblock domains of Rag GTPases: helix α1 of p18 and the two helices side of MP1-p14...
November 9, 2017: Nature Communications
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