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https://www.readbyqxmd.com/read/29242283/phase-ii-study-of-bez235-versus-everolimus-in-patients-with-mammalian-target-of-rapamycin-inhibitor-na%C3%A3-ve-advanced-pancreatic-neuroendocrine-tumors
#1
Ramon Salazar, Rocio Garcia-Carbonero, Steven K Libutti, Andrew E Hendifar, Ana Custodio, Rosine Guimbaud, Catherine Lombard-Bohas, Sergio Ricci, Heinz-Josef Klümpen, Jaume Capdevila, Nicholas Reed, Annemiek Walenkamp, Enrique Grande, Sufiya Safina, Tim Meyer, Oliver Kong, Herve Salomon, Ranjana Tavorath, James C Yao
LESSONS LEARNED: Treatment with BEZ235 has not been shown to demonstrate increased efficacy compared with everolimus and may be associated with a poorer tolerability profile.The hypothesis of dual targeting of the phosphatidylinositol 3-kinase and mammalian target of rapamycin pathways in patients with advanced pancreatic neuroendocrine tumors may warrant further study using other agents. BACKGROUND: This phase II study investigated whether targeting the phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway via PI3K, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) inhibition using BEZ235 may be more effective than mTORC1 inhibition with everolimus in patients with advanced pancreatic neuroendocrine tumors (pNET) who are naïve to mTOR inhibitor therapy...
December 14, 2017: Oncologist
https://www.readbyqxmd.com/read/29241828/acute-and-chronic-rapamycin-use-in-patients-with-fibrodysplasia-ossificans-progressiva-a-report-of-two-cases
#2
REVIEW
Frederick S Kaplan, Leonid Zeitlin, Stephen P Dunn, Shira Benor, David Hagin, Mona Al Mukaddam, Robert J Pignolo
Fibrodysplasia Ossificans Progressiva (FOP) is an ultrarare genetic disorder of progressive, disabling heterotopic ossification for which there is presently no definitive treatment. Several recent studies in genetic mouse models of FOP support involvement of the mechanistic target of rapamycin complex 1 (mTORC1) pathway in the pathophysiology of FOP and propose the repurposed use of rapamycin, an inhibitor of mTORC1 signaling in clinical trials for the management of FOP. Here we report two patients with the classic FOP mutation who received rapamycin-one for four months on a compassionate basis for treatment of acute flare-ups of the neck and back that were refractory to corticosteroid therapy-and the other for 18years for chronic immunosuppression following liver transplantation for intercurrent cytomegalovirus infection...
December 11, 2017: Bone
https://www.readbyqxmd.com/read/29241749/acne-vulgaris-the-metabolic-syndrome-of-the-pilosebaceous-follicle
#3
Bodo C Melnik
Acne vulgaris is an epidemic inflammatory disease of the human sebaceous follicle and represents the most common skin disease affecting about 85% of adolescents in Westernized populations. Acne vulgaris is primarily a disease of wealthy countries and exhibits higher prevalence rates in developed compared with developing countries. No acne has been found in non-Westernized populations still living under Paleolithic dietary conditions constraining hyperglycemic carbohydrates, milk, and dairy products. The high prevalence rates of adolescent acne cannot be explained by the predominance of genetic factors but by the influence of a Western diet that overstimulates the key conductor of metabolism, the nutrient- and growth factor-sensitive kinase mTORC1...
January 2018: Clinics in Dermatology
https://www.readbyqxmd.com/read/29241457/impaired-regeneration-in-calpain-3-null-muscle-is-associated-with-perturbations-in-mtorc1-signaling-and-defective-mitochondrial-biogenesis
#4
Mehmet E Yalvac, Jakkrit Amornvit, Cilwyn Braganza, Lei Chen, Syed-Rehan A Hussain, Kimberly M Shontz, Chrystal L Montgomery, Kevin M Flanigan, Sarah Lewis, Zarife Sahenk
BACKGROUND: Previous studies in patients with limb-girdle muscular dystrophy type 2A (LGMD2A) have suggested that calpain-3 (CAPN3) mutations result in aberrant regeneration in muscle. METHODS: To gain insight into pathogenesis of aberrant muscle regeneration in LGMD2A, we used a paradigm of cardiotoxin (CTX)-induced cycles of muscle necrosis and regeneration in the CAPN3-KO mice to simulate the early features of the dystrophic process in LGMD2A. The temporal evolution of the regeneration process was followed by assessing the oxidative state, size, and the number of metabolic fiber types at 4 and 12 weeks after last CTX injection...
December 14, 2017: Skeletal Muscle
https://www.readbyqxmd.com/read/29238469/the-role-of-sirolimus-in-proteinuria-in-diabetic-nephropathy-rats
#5
JinJun Wang, ZiQiang Xu, BiCheng Chen, ShaoLing Zheng, Peng Xia, Yong Cai
Objectives: The aim of this study was to observe the impact of sirolimus on proteinuria in streptozotocin (STZ) induced diabetic rats. Materials and Methods: Rats were given a single injection of STZ to induce diabetic rat model. Rats' 24 hr urine was collected to test, urinary and the kidney tissues were harvested at the 8th and 20th weeks, respectively. Podocyte morphological changes were examined by electron microscopy and the ZO-1, podocin expressions in kidneys were detected by immunohistochemistry; the protein levels of Raptor and pS6 were measured by Western blot assay...
December 2017: Iranian Journal of Basic Medical Sciences
https://www.readbyqxmd.com/read/29236692/mechanisms-of-mtorc1-activation-by-rheb-and-inhibition-by-pras40
#6
Haijuan Yang, Xiaolu Jiang, Buren Li, Hyo J Yang, Meredith Miller, Angela Yang, Ankita Dhar, Nikola P Pavletich
The mechanistic target of rapamycin complex 1 (mTORC1) controls cell growth and metabolism in response to nutrients, energy levels, and growth factors. It contains the atypical kinase mTOR and the RAPTOR subunit that binds to the Tor signalling sequence (TOS) motif of substrates and regulators. mTORC1 is activated by the small GTPase RHEB (Ras homologue enriched in brain) and inhibited by PRAS40. Here we present the 3.0 ångström cryo-electron microscopy structure of mTORC1 and the 3.4 ångström structure of activated RHEB-mTORC1...
December 13, 2017: Nature
https://www.readbyqxmd.com/read/29234390/astragaloside-iv-ameliorates-airway-inflammation-in-an-established-murine-model-of-asthma-by-inhibiting-the-mtorc1-signaling-pathway
#7
Hualiang Jin, Limin Wang, Bei Li, Cui Cai, Jian Ye, Junbo Xia, Shenglin Ma
Astragaloside IV (AS-IV), a main active constituent of Astragalus membranaceus, has been confirmed to have antiasthmatic effects. However, it remained unclear whether the beneficial effects of AS-IV on asthma were attributed to the mTOR inhibition; this issue was the focus of the present work. BALB/c mice were sensitized and challenged with ovalbumin followed with 3 weeks of rest/recovery and then reexposure to ovalbumin. AS-IV was administrated during the time of rest and reexposure. The characteristic features of allergic asthma, including airway hyperreactivity, histopathology, cytokines (IL-4, IL-5, IL-13, IL-17, and INF-γ), and CD4+CD25+Foxp3+Treg cells in bronchoalveolar lavage fluid (BALF), and downstream proteins of mTORC1/2 signaling were examined...
2017: Evidence-based Complementary and Alternative Medicine: ECAM
https://www.readbyqxmd.com/read/29233879/exploiting-cancer-vulnerabilities-mtor-autophagy-and-homeostatic-imbalance
#8
REVIEW
Charlotte E Johnson, Andrew R Tee
Mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) at lysosomes plays a pivotal role in cell growth control where an array of large multiprotein complexes relay nutrient, energy, and growth signal inputs through mTORC1. In cancer cells, such regulation often becomes disconnected, leading to uncontrolled cell growth and an elevation in cellular stress. Consequently, cancer cells often lose homeostatic balance as they grow in unfavorable conditions, i.e. when nutrients and energy are limited yet mTORC1 is still aberrantly activated...
December 12, 2017: Essays in Biochemistry
https://www.readbyqxmd.com/read/29233869/mtorc1-as-the-main-gateway-to-autophagy
#9
REVIEW
Yoana Rabanal-Ruiz, Elsje G Otten, Viktor I Korolchuk
Cells and organisms must coordinate their metabolic activity with changes in their environment to ensure their growth only when conditions are favourable. In order to maintain cellular homoeostasis, a tight regulation between the synthesis and degradation of cellular components is essential. At the epicentre of the cellular nutrient sensing is the mechanistic target of rapamycin complex 1 (mTORC1) which connects environmental cues, including nutrient and growth factor availability as well as stress, to metabolic processes in order to preserve cellular homoeostasis...
December 12, 2017: Essays in Biochemistry
https://www.readbyqxmd.com/read/29233655/recombinant-human-erythropoietin-protects-against-brain-injury-through-blunting-the-mtorc1-pathway-in-the-developing-brains-of-rats-with-seizures
#10
Qinrui Li, Ying Han, Junbao Du, Hongfang Jin, Jing Zhang, Manman Niu, Jiong Qin
AIMS: Recurrent seizures can result in neuronal death, cognitive deficits and intellectual disability, which causes devastating damage in children. Recombinant human erythropoietin (rhEPO) is considered a neuroprotective factor in many nervous system diseases. However, the precise mechanisms through which rhEPO exerts its neuroprotective effects on epilepsy remain unknown. Thus, in this study, we determined whether rhEPO protects against brain injury by inducing cortical neuronal autophagy through blunting the mammalian target of rapamycin complex 1 (mTORC1) pathway in the developing brains of rats with seizures...
December 9, 2017: Life Sciences
https://www.readbyqxmd.com/read/29228564/inhibitors-of-the-pi3k-mtor-pathway-prevent-stat5-phosphorylation-in-jak2v617f-mutated-cells-through-pp2a-cip2a-axis
#11
Niccolò Bartalucci, Laura Calabresi, Manjola Balliu, Serena Martinelli, Maria Caterina Rossi, Jean Luc Villeval, Francesco Annunziato, Paola Guglielmelli, Alessandro M Vannucchi
Inhibition of the constitutively activated JAK/STAT pathway in JAK2V617F mutated cells by the JAK1/JAK2 inhibitor ruxolitinib resulted in clinical benefits in patients with myeloproliferative neoplasms. However, evidence of disease-modifying effects remains scanty; furthermore, some patients do not respond adequately to ruxolitinib, or have transient responses, thus novel treatment strategies are needed. Here we demonstrate that ruxolitinib causes incomplete inhibition of STAT5 in JAK2V617F mutated cells due to persistence of phosphorylated serine residues of STAT5b, that conversely are targeted by PI3K and mTORC1 inhibitors...
November 14, 2017: Oncotarget
https://www.readbyqxmd.com/read/29228105/metformin-attenuates-susceptibility-to-inflammation-induced-preterm-birth-in-mice-with-higher-endocannabinoid-levels
#12
Xiaofei Sun, Alexandra Tavenier, Wenbo Deng, Emma Leishman, Heather B Bradshaw, Sudhansu K Dey
Premature decidual senescence is a contributing factor to preterm birth. Fatty acid amide hydrolase mutant females (Faah-/-) with higher endocannabinoid levels are also more susceptible to preterm birth upon lipopolysaccharide (LPS) challenge due to enhanced decidual senescence; this is associated with MAPK p38 activation. Previous studies have shown that mammalian target of rapamycin complex 1 (mTORC1) contributes to decidual senescence and promotes the incidence of preterm birth. In the present study, we sought to attenuate premature decidual aging in Faah-/- females by targeting mTORC1 and p38 signaling pathways...
December 5, 2017: Biology of Reproduction
https://www.readbyqxmd.com/read/29224866/the-effects-of-l-type-amino-acid-transporter-1-on-milk-protein-synthesis-in-mammary-glands-of-dairy-cows
#13
Ye Lin, Xiaoyu Duan, He Lv, Yang Yang, Ying Liu, Xuejun Gao, Xiaoming Hou
The mammary gland requires the uptake of AA for milk protein synthesis during lactation. The L-type amino acid transporter 1 (LAT1, encoded by SLC7A5), found in many different types of mammalian cells, is indispensable as a transporter of essential AA to maintain cell growth and protein synthesis. However, the function of LAT1 in regulating milk protein synthesis in the mammary gland of the dairy cow remains largely unknown. For the current study, we characterized the relationship between LAT1 expression and milk protein synthesis in lactating dairy cows and investigated whether the mammalian target of rapamycin complex1 (mTORC1) signaling controls the expression of LAT1 in their mammary glands...
December 7, 2017: Journal of Dairy Science
https://www.readbyqxmd.com/read/29222328/fructose-and-glucose-regulate-mammalian-target-of-rapamycin-complex-1-and-can-activate-lipogenic-gene-expression-via-distinct-pathways
#14
Yue Hu, Ivana Semova, Xiaowei Sun, Hong Kang, Satyapal Chahar, Anthony N Hollenberg, David Masson, Matthew D Hirschey, Ji Miao, Sudha B Biddinger
Though calorically equivalent to glucose, fructose appears to be more lipogenic, leading to dyslipidemia, fatty liver disease, cardiovascular disease, and diabetes. To better understand how fructose induces lipogenesis, we compared the effects of fructose and glucose on the mTORC1 signaling node, a central regulator of lipogenesis. We found that fructose acutely and transiently suppressed mTORC1 signaling in vitro and in vivo. The constitutive activation of mTORC1 reduced hepatic lipogenic gene expression and produced hypotriglyceridemia after one week of fructose feeding...
December 8, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29222166/effect-of-il-7-therapy-on-phospho-ribosomal-protein-s6-and-traf1-expression-in-hiv-specific-cd8-t-cells-in-patients-receiving-antiretroviral-therapy
#15
Chao Wang, Maria I Edilova, Lisa E Wagar, Shariq Mujib, Meromit Singer, Nicole F Bernard, Thérèse Croughs, Michael M Lederman, Irini Sereti, Margaret A Fischl, Elisabeth Kremmer, Mario Ostrowski, Jean-Pierre Routy, Tania H Watts
IL-7 therapy has been evaluated in patients who do not regain normal CD4 T cell counts after virologically successful antiretroviral therapy. IL-7 increases total circulating CD4 and CD8 T cell counts; however, its effect on HIV-specific CD8 T cells has not been fully examined. TRAF1, a prosurvival signaling adaptor required for 4-1BB-mediated costimulation, is lost from chronically stimulated virus-specific CD8 T cells with progression of HIV infection in humans and during chronic lymphocytic choriomeningitis infection in mice...
December 8, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29222112/rheb-localized-on-the-golgi-membrane-activates-lysosome-localized-mtorc1-at-the-golgi-lysosome-contact-site
#16
Feike Hao, Kazuhiko Kondo, Takashi Itoh, Sumiko Ikari, Shigeyuki Nada, Masato Okada, Takeshi Noda
In response to amino acid supply, mTORC1, a master regulator of cell growth, is recruited to the lysosome and activated by a small GTPase, Rheb. However, the intracellular localization of Rheb is controversial. In this study, we showed that a significant portion of Rheb was localized on the Golgi but not on the lysosome. GFP-Rheb could activate mTORC1, even when forced to exclusively localize to the Golgi. Likewise, artificial recruitment of mTORC1 to the Golgi allowed its activation. Accordingly, the Golgi was in contact with the lysosome at the newly described Golgi lysosome contact site (GLCS)...
December 8, 2017: Journal of Cell Science
https://www.readbyqxmd.com/read/29221131/hoxa5-increases-mitochondrial-apoptosis-by-inhibiting-akt-mtorc1-s6k1-pathway-in-mice-white-adipocytes
#17
Fei Feng, Qian Ren, Song Wu, Muhammad Saeed, Chao Sun
Homeobox A5(Hoxa5), a member of the Hox family, plays a important role in the regulation of proliferation and apoptosis in cancer cells. The dysregulation of the adipocyte apoptosis in vivo leads to obesity and metabolic disorders. However, the effects of Hoxa5 on adipocyte apoptosis are still unknown. In this study, palmitic acid (PA) significantly increased the mRNA level of Hoxa5 and triggered white adipocyte apoptosis in vivo and in vitro. Further analysis revealed that Hoxa5 enhanced the early and late apoptotic cells and fragmentation of genomic DNA in adipocytes from inguinal white adipose tissue (iWAT) of mice...
November 10, 2017: Oncotarget
https://www.readbyqxmd.com/read/29220665/mtorc1-activation-during-repeated-regeneration-impairs-somatic-stem-cell-maintenance
#18
Samantha Haller, Subir Kapuria, Rebeccah R Riley, Monique N O'Leary, Katherine H Schreiber, Julie K Andersen, Simon Melov, Jianwen Que, Thomas A Rando, Jason Rock, Brian K Kennedy, Joseph T Rodgers, Heinrich Jasper
The balance between self-renewal and differentiation ensures long-term maintenance of stem cell (SC) pools in regenerating epithelial tissues. This balance is challenged during periods of high regenerative pressure and is often compromised in aged animals. Here, we show that target of rapamycin (TOR) signaling is a key regulator of SC loss during repeated regenerative episodes. In response to regenerative stimuli, SCs in the intestinal epithelium of the fly and in the tracheal epithelium of mice exhibit transient activation of TOR signaling...
December 7, 2017: Cell Stem Cell
https://www.readbyqxmd.com/read/29215029/mtorc1-signaling-is-a-critical-regulator-of-postnatal-tendon-development
#19
Joohyun Lim, Elda Munivez, Ming-Ming Jiang, I-Wen Song, Francis Gannon, Douglas R Keene, Ronen Schweitzer, Brendan H Lee, Kyu Sang Joeng
Tendons transmit contractile forces between musculoskeletal tissues. Whereas the biomechanical properties of tendons have been studied extensively, the molecular mechanisms regulating postnatal tendon development are not well understood. Here we examine the role of mTORC1 signaling in postnatal tendon development using mouse genetic approaches. Loss of mTORC1 signaling by removal of Raptor in tendons caused severe tendon defects postnatally, including decreased tendon thickness, indicating that mTORC1 is necessary for postnatal tendon development...
December 7, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29212209/targeted-inhibition-of-glutaminase-as-a-potential-new-approach-for-the-treatment-of-nf1-associated-soft-tissue-malignancies
#20
Tahir N Sheikh, Parag P Patwardhan, Serge Cremers, Gary K Schwartz
Many cancer cells rely on glutamine as the source of carbon molecules to feed the biosynthetic pathways and are often addicted to glutaminolysis. Inhibitors of glutaminase activity have gained attention in the last few years due to their anti-proliferative effect and ability to induce apoptosis in some cancers. Although it is a promising therapeutic approach, its efficacy or the role played by glutamine in modulating cell proliferation in NF1 associated tumors has never been studied. We report for the first time, a strong correlation between the NF1 status of tumor cells and increased sensitivity to glutamine deprivation and glutaminase inhibition...
November 7, 2017: Oncotarget
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