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https://www.readbyqxmd.com/read/27926859/rapamycin-reverses-metabolic-deficits-in-lamin-a-c-deficient-mice
#1
Chen-Yu Liao, Sydney S Anderson, Nicole H Chicoine, Jarrott R Mayfield, Emmeline C Academia, Joy A Wilson, Chalermkwan Pongkietisak, Morgan A Thompson, Earl P Lagmay, Delana M Miller, Yueh-Mei Hsu, Mark A McCormick, Monique N O'Leary, Brian K Kennedy
The role of the mTOR inhibitor, rapamycin, in regulation of adiposity remains controversial. Here, we evaluate mTOR signaling in lipid metabolism in adipose tissues of Lmna(-/-) mice, a mouse model for dilated cardiomyopathy and muscular dystrophy. Lifespan extension by rapamycin is associated with increased body weight and fat content, two phenotypes we link to suppression of elevated energy expenditure. In both white and brown adipose tissue of Lmna(-/-) mice, we find that rapamycin inhibits mTORC1 but not mTORC2, leading to suppression of elevated lipolysis and restoration of thermogenic protein UCP1 levels, respectively...
December 6, 2016: Cell Reports
https://www.readbyqxmd.com/read/27923036/cotargeting-of-cyp-19-aromatase-and-emerging-pivotal-signalling-pathways-in-metastatic-breast-cancer
#2
REVIEW
Stine Daldorff, Randi Margit Ruud Mathiesen, Olav Erich Yri, Hilde Presterud Ødegård, Jürgen Geisler
Aromatase inhibition is one of the cornerstones of modern endocrine therapy of oestrogen receptor-positive (ER+) metastatic breast cancer (MBC). The nonsteroidal aromatase inhibitors anastrozole and letrozole, as well as the steroidal aromatase inactivator exemestane, are the preferred drugs and established worldwide in all clinical phases of the disease. However, although many patients suffering from MBC experience an initial stabilisation of their metastatic burden, drug resistance and disease progression occur frequently, following in general only a few months on treatment...
December 6, 2016: British Journal of Cancer
https://www.readbyqxmd.com/read/27922821/identification-of-salvia-haenkei-as-gerosuppressant-agent-by-using-an-integrated-senescence-screening-assay
#3
Ivana Matic, Ajinkya Revandkar, Jingjing Chen, Angela Bisio, Stefano Dall'Acqua, Veronica Cocetta, Paola Brun, Giorgio Mancino, Martina Milanese, Maurizio Mattei, Monica Montopoli, Andrea Alimonti
Cellular senescence is a stable cell cycle arrest that is the causative process of aging. The PI3K/AKT/mTOR pathway is implicated in the control of cellular senescence and inhibitors of this pathway have been successfully used for life span prolongation experiments in mammals. PTEN is the major regulator of the PI3K/AKT/mTOR pathway and loss of PTEN promotes a senescence response termed PICS. Here we report a novel-screening assay, for the identification of compounds that block different types of senescence response...
December 1, 2016: Aging
https://www.readbyqxmd.com/read/27922010/mek-inhibitors-block-growth-of-lung-tumours-with-mutations-in-ataxia-telangiectasia-mutated
#4
Michal Smida, Ferran Fece de la Cruz, Claudia Kerzendorfer, Iris Z Uras, Barbara Mair, Abdelghani Mazouzi, Tereza Suchankova, Tomasz Konopka, Amanda M Katz, Keren Paz, Katalin Nagy-Bojarszky, Markus K Muellner, Zsuzsanna Bago-Horvath, Eric B Haura, Joanna I Loizou, Sebastian M B Nijman
Lung cancer is the leading cause of cancer deaths, and effective treatments are urgently needed. Loss-of-function mutations in the DNA damage response kinase ATM are common in lung adenocarcinoma but directly targeting these with drugs remains challenging. Here we report that ATM loss-of-function is synthetic lethal with drugs inhibiting the central growth factor kinases MEK1/2, including the FDA-approved drug trametinib. Lung cancer cells resistant to MEK inhibition become highly sensitive upon loss of ATM both in vitro and in vivo...
December 6, 2016: Nature Communications
https://www.readbyqxmd.com/read/27921039/clinical-manifestation-and-management-of-adpkd-in-western-countries
#5
REVIEW
Claudia Sommerer, Martin Zeier
BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disease in Western countries. The prevalence is between 2.4/10,000 and 3.9/10,000. ADPKD represents a systemic disease resulting in deterioration in renal function. Until now, mutations in two genes (PKD1 and PKD2) have been identified. Recently, the European Medicines Agency (EMA) approved the use of the vasopressin V2 receptor antagonist tolvaptan to slow the progression of cyst development and renal insufficiency connected with ADPKD in adult patients with chronic kidney disease stages 1-3 at initiation of treatment with evidence of rapidly progressing disease...
October 2016: Kidney Diseases
https://www.readbyqxmd.com/read/27921038/the-clinical-manifestation-and-management-of-autosomal-dominant-polycystic-kidney-disease-in-china
#6
REVIEW
Cheng Xue, Chen-Chen Zhou, Ming Wu, Chang-Lin Mei
BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic hereditary kidney disease characterized by progressive enlargement of renal cysts. The incidence is 1-2‰ worldwide. Mutations in two genes (PKD1 and PKD2) cause ADPKD. Currently, there is no pharmaceutical treatment available for ADPKD patients in China. Summary: This review focused on advances in clinical manifestation, gene diagnosis, risk factors, and management of ADPKD in China. There is an age-dependent increase in total kidney volume (TKV) and decrease in renal function in Chinese ADPKD patients...
October 2016: Kidney Diseases
https://www.readbyqxmd.com/read/27920721/commentary-overcoming-mtor-resistance-mutations-with-a-new-generation-mtor-inhibitor
#7
COMMENT
Maurizio Renna
No abstract text is available yet for this article.
2016: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/27920423/de-novo-renal-neoplasia-after-kidney-transplantation-according-to-new-2016-who-classification-of-renal-tumors
#8
Albino Eccher, Luigino Boschiero, Brett Delahunt, Luca Cima, Francesca Fior, Francesco Nacchia, Momo Rostand, Amedeo Carraro, Umberto Tedeschi, Gianluigi Zaza, Marilena Casartelli Liviero, Laura Zampicinini, Marco Chilosi, Giuseppe Feltrin, Claudio Rago, Antonietta D'Errico, Claudio Ghimenton, Guido Martignoni, Matteo Brunelli
BACKGROUND De novo renal neoplasia developing after kidney transplantation at Verona Kidney Transplant Center were reviewed according to new 2016 WHO Renal Tumor Classification. MATERIAL AND METHODS Primary renal tumors developed in native or transplanted kidneys de novo following renal transplantation were retrieved and histologically reviewed by three expert uropathologists. Immunoexpression of the diagnostic antigens CD13, CD10, CK7, CK34bE12, AMACR, CAIX, AE1/AE3, CK14, GATA-3, HMB-45, cathepsin-k, S100A1, and parvalbumin was assessed...
December 6, 2016: Annals of Transplantation: Quarterly of the Polish Transplantation Society
https://www.readbyqxmd.com/read/27916907/metformin-inhibits-tgf-%C3%AE-1-induced-epithelial-to-mesenchymal-transition-via-pkm2-relative-mtor-p70s6k-signaling-pathway-in-cervical-carcinoma-cells
#9
Keyan Cheng, Min Hao
BACKGROUND: Epithelial-to-mesenchymal transition (EMT) plays a prominent role in tumorigenesis. Metformin exerts antitumorigenic effects in various cancers. This study investigated the mechanisms of metformin in TGF-β1-induced Epithelial-to-mesenchymal transition (EMT) in cervical carcinoma cells. METHODS: cells were cultured with 10 ng/mL TGF-β1 to induce EMT and treated with or without metformin. Cell viability was evaluated by CCK-8 (Cell Counting Kit 8, CCK-8) assay; apoptosis were analyzed by flow cytometry; cell migration was evaluated by wound-healing assay...
November 30, 2016: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/27915972/resistance-to-cell-death-and-its-modulation-in-cancer-stem-cells
#10
Ahmad R Safa
Accumulating evidence has demonstrated that human cancers arise from various tissues of origin that initiate from cancer stem cells (CSCs) or cancer-initiating cells. The extrinsic and intrinsic apoptotic pathways are dysregulated in CSCs, and these cells play crucial roles in tumor initiation, progression, cell death resistance, chemo- and radiotherapy resistance, and tumor recurrence. Understanding CSC-specific signaling proteins and pathways is necessary to identify specific therapeutic targets that may lead to the development of more efficient therapies selectively targeting CSCs...
2016: Critical Reviews in Oncogenesis
https://www.readbyqxmd.com/read/27915035/hyperinsulinaemic-hypoglycaemia-in-children-and-adults
#11
REVIEW
Pratik Shah, Sofia A Rahman, Huseyin Demirbilek, Maria Güemes, Khalid Hussain
Pancreatic β cells are functionally programmed to release insulin in response to changes in plasma glucose concentration. Insulin secretion is precisely regulated so that, under normal physiological conditions, fasting plasma glucose concentrations are kept within a narrow range of 3·5-5·5 mmol/L. In hyperinsulinaemic hypoglycaemia, insulin secretion becomes dysregulated (ie, uncoupled from glucose metabolism) so that insulin secretion persists in the presence of low plasma glucose concentrations. Hyperinsulinaemic hypoglycaemia is the most common cause of severe and persistent hypoglycaemia in neonates and children...
November 30, 2016: Lancet Diabetes & Endocrinology
https://www.readbyqxmd.com/read/27914823/rapamycin-inhibits-the-proliferation-of-endothelial-cells-in-hemangioma-by-blocking-the-mtor-fabp4-pathway
#12
Ying Wang, Jiarui Chen, Weiqing Tang, Yanping Zhang, Xiaoyan Li
FABP4 is widely expressed in both normal and pathologic tissues. It promotes cell proliferation, survival and migration of endothelial cells, and therefore, angiogenesis. However, the role of FABP4 in hemangioma or hemangioma endothelial cells (HemECs) has not been explored. In this study, we investigated whether FABP4 directly regulates the proliferation of HemECs. The expression of cell cycle checkpoint genes was analyzed with the microarray data of human dermal microvascular endothelial cells (HDVECs) and infantile hemangioma endothelial cells...
November 30, 2016: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
https://www.readbyqxmd.com/read/27914215/lysine-specific-demethylase-1-lsd1-inhibitor-s2101-induces-autophagy-via-the-akt-mtor-pathway-in-skov3-ovarian-cancer-cells
#13
Shujun Feng, Ye Jin, Mengjiao Cui, Jianhua Zheng
BACKGROUND S2101 is one of the most potent LSD1 inhibitors, which can inhibit ovarian cancer cells viability. This study aimed to detect the mechanism behind the anticancer properties of S2101 in SKOV3 ovarian cells. MATERIAL AND METHODS Cell viability was tested by Cell Counting Kit-8 (CCK-8) assay. Cellular apoptosis and autophagy were evaluated by flow cytometric analysis using Annexin-V/PI staining methods and Green fluorescent protein (GFP)-fused-LC3 (GFP-LC3), respectively. Western blotting was performed for analyzing the Bax, Bcl-2, mTOR, p- mTOR, p62, LC3-I, LC3-II, AKT, and p-AKT protein expression...
December 3, 2016: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
https://www.readbyqxmd.com/read/27913436/erk-and-p38-mapk-activities-determine-sensitivity-to-pi3k-mtor-inhibition-via-regulation-of-myc-and-yap
#14
Taru Muranen, Laura M Selfors, Julie Hwang, Lisa L Gallegos, Jonathan L Coloff, Carson C Thoreen, Seong A Kang, David M Sabatini, Gordon B Mills, Joan S Brugge
Aberrant activation of the PI3K/mTOR pathway is a common feature of many cancers and an attractive target for therapy, but resistance inevitably evolves as is the case for any cancer cell-targeted therapy. In animal tumor models, chronic inhibition of PI3K/mTOR initially inhibits tumor growth, but over time, tumor cells escape inhibition. In this study, we identified a context-dependent mechanism of escape whereby tumor cells upregulated the proto-oncogene transcriptional regulators c-MYC and YAP1. This mechanism was dependent on both constitutive ERK activity as well as inhibition of the stress kinase p38...
October 20, 2016: Cancer Research
https://www.readbyqxmd.com/read/27913296/regulation-of-skeletal-muscle-insulin-stimulated-signaling-through-the-mek-redd1-mtor-axis
#15
Cory M Dungan, David L Williamson
Recent findings in adipocytes suggest that mitogen-activated protein kinase (MAPK)/extracellular-regulated signaling kinase (ERK) kinase 1/2 (MEK1/2) signaling regulates regulated in development and DNA damage 1 (REDD1) protein expression. Similarly, our previous work show that a lack of REDD1 protein expression, and associated hyperactive basal mechanistic target of rapamycin (mTOR) signaling, limits skeletal muscle's response to insulin. Therefore, we sought to determine: 1) if MEK1/2 inhibition is sufficient to reduce REDD1 protein expression and subsequently insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation via negative feedback of hyperactive mTOR in REDD1 wild-type (WT) mice and 2) if rapamycin-mediated mTOR inhibition is sufficient to improve IRS-1 tyrosine phosphorylation in REDD1 knockout (KO) mice...
November 29, 2016: Biochemical and Biophysical Research Communications
https://www.readbyqxmd.com/read/27913276/association-of-genetic-polymorphisms-of-angiopoietin-like-4-with-severity-of-posttransplant-proteinuria-in-kidney-allograft-recipients
#16
Youngil Chang, Tariq Shah, Jaewook Yang, David I Min
BACKGROUND: Proteinuria is a hallmark of glomerular injury, and persistent proteinuria is associated with graft failure in kidney transplant patients. Recently, it is known that the level of circulating angiopoietin-like 4 (ANGPTL4) is elevated in the patients with human nephrotic syndrome, in which ANGPTL4 is responsible for relieving proteinuria. PURPOSE: The purpose of this study is to determine effects of clinical factors and genetic polymorphism of ANGPTL4 on proteinuria after kidney transplantation...
November 29, 2016: Transplant Immunology
https://www.readbyqxmd.com/read/27911276/the-mtor-inhibitor-everolimus-in-combination-with-azacitidine-in-patients-with-relapsed-refractory-acute-myeloid-leukemia-a-phase-ib-ii-study
#17
Peter Tan, Ing Soo Tiong, Shaun Fleming, Giovanna Pomilio, Nik Cummings, Mark Droogleever, Julie McManus, Anthony Schwarer, John Catalano, Sushrut Patil, Sharon Avery, Andrew Spencer, Andrew Wei
Therapeutic options are limited in relapsed/refractory acute myeloid leukemia (AML). We evaluated the maximum tolerated dose (MTD) and preliminary efficacy of mammalian target of rapamycin (mTOR) inhibitor, everolimus (days 5-21) in combination with azacitidine 75 mg/m2 subcutaneously (days 1-5 and 8-9 every 28 days) in 40 patients with relapsed (n = 27), primary refractory (n = 11) or elderly patients unfit for intensive chemotherapy (n = 2). MTD was not reached following everolimus dose escalation (2.5, 5 or 10 mg; n = 19) to the 10 mg dose level which was expanded (n = 21)...
November 29, 2016: Oncotarget
https://www.readbyqxmd.com/read/27906677/the-implication-of-flt3-amplification-for-flt-targeted-therapeutics-in-solid-tumors
#18
Sung Hee Lim, Sun-Young Kim, Kyung Kim, Hyojin Jang, Soomin Ahn, Kyoung-Mee Kim, Nayoung K D Kim, Woongyang Park, Su Jin Lee, Seung Tae Kim, Se Hoon Park, Joon Oh Park, Young Suk Park, Se-Hoon Lee, Ho Yeong Lim, Keunchil Park, Won Ki Kang, Jeeyun Lee
We investigated the patients with solid cancers harboring Fms-like tyrosine kinase 3 (FLT3) amplification using targeted sequencing of tumor tissue specimen and FISH assay. Simultaneously, FLT3-amplified patient-derived cells (PDCs) were generated to evaluate the sensitivity to FLT3 inhibition. A patient with metastatic colon cancer who was previously treated with more than 3rd line cytotoxic chemotherapy was found to have FLT3 amplification and then received regorafenib showing partial response. In two PDC cell lines with FLT3 amplification, FLT3 mRNA expression was increased, however, the growth of tumor cells was not significantly inhibited by either regorafenib or sorafenib which is known to block the activity FLT3...
November 29, 2016: Oncotarget
https://www.readbyqxmd.com/read/27906078/four-week-rapamycin-treatment-improves-muscular-dystrophy-in-a-fukutin-deficient-mouse-model-of-dystroglycanopathy
#19
Steven J Foltz, Junna Luan, Jarrod A Call, Ankit Patel, Kristen B Peissig, Marisa J Fortunato, Aaron M Beedle
BACKGROUND: Secondary dystroglycanopathies are a subset of muscular dystrophy caused by abnormal glycosylation of α-dystroglycan (αDG). Loss of αDG functional glycosylation prevents it from binding to laminin and other extracellular matrix receptors, causing muscular dystrophy. Mutations in a number of genes, including FKTN (fukutin), disrupt αDG glycosylation. METHODS: We analyzed conditional Fktn knockout (Fktn KO) muscle for levels of mTOR signaling pathway proteins by Western blot...
June 2, 2016: Skeletal Muscle
https://www.readbyqxmd.com/read/27906072/actrii-blockade-protects-mice-from-cancer-cachexia-and-prolongs-survival-in-the-presence-of-anti-cancer-treatments
#20
Shinji Hatakeyama, Serge Summermatter, Marie Jourdain, Stefan Melly, Giulia C Minetti, Estelle Lach-Trifilieff
BACKGROUND: Cachexia affects the majority of patients with advanced cancer and is associated with reduced treatment tolerance, response to therapy, quality of life, and life expectancy. Cachectic patients with advanced cancer often receive anti-cancer therapies against their specific cancer type as a standard of care, and whether specific ActRII inhibition is efficacious when combined with anti-cancer agents has not been elucidated yet. METHODS: In this study, we evaluated interactions between ActRII blockade and anti-cancer agents in CT-26 mouse colon cancer-induced cachexia model...
July 26, 2016: Skeletal Muscle
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