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https://www.readbyqxmd.com/read/28213521/signalling-adaptor-shcd-suppresses-erk-phosphorylation-distal-to-the-ret-and-trk-neurotrophic-receptors
#1
Melanie K B Wills, Ava Keyvani Chahi, Hayley R Lau, Manali Tilak, Brianna Guild, Laura A New, Peihua Lu, Keévin Jacquet, Susan O Meakin, Nicolas Bisson, Nina Jones
Proteins of the Shc family are typically involved in signal transduction events involving Ras/MAPK and PI3K/Akt pathways. In the nervous system, they function proximal to the neurotrophic factors that regulate cell survival, differentiation, and neuron-specific characteristics. The least-characterized homolog, ShcD, is robustly expressed in the developing and mature nervous system, but its contributions to neural cell circuitry are largely uncharted. We now report that ShcD binds to active Ret, TrkA, and TrkB neurotrophic factor receptors predominantly via its phosphotyrosine binding (PTB) domain...
February 17, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28213494/plc%C3%AE%C2%B51-regulates-sdf-1%C3%AE-induced-lymphocyte-adhesion-and-migration-to-sites-of-inflammation
#2
Marianne Strazza, Inbar Azoulay-Alfaguter, Michael Peled, Alan V Smrcka, Edward Y Skolnik, Shekhar Srivastava, Adam Mor
Regulation of integrins is critical for lymphocyte adhesion to endothelium and migration throughout the body. Inside-out signaling to integrins is mediated by the small GTPase Ras-proximate-1 (Rap1). Using an RNA-mediated interference screen, we identified phospholipase Cε 1 (PLCε1) as a crucial regulator of stromal cell-derived factor 1 alpha (SDF-1α)-induced Rap1 activation. We have shown that SDF-1α-induced activation of Rap1 is transient in comparison with the sustained level following cross-linking of the antigen receptor...
February 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28213365/fda-approval-summary-tas-102
#3
Leigh Marcus, Steven J Lemery, Sachia Khasar, Emily Wearne, Whitney S Helms, Weishi Yuan, Kun He, Xianhua Cao, Jingyu Yu, Hong Zhao, Yaning Wang, Olen Stephens, Erika Englund, Rajiv Agarwal, Patricia Keegan, Richard Pazdur
FDA approved TAS-102 (Lonsurf, Taiho Oncology, Inc.) for the treatment of patients with metastatic colorectal cancer (mCRC) who have been previously treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy. In an international, multicenter, double-blinded, placebo-controlled trial (TPU-TAS-102-301, herein referred to as RECOURSE), 800 patients with previously treated mCRC were randomly allocated (2:1) to receive either TAS-102 35mg/m2 orally twice daily after meals on Days 1-5 and 8-12 of each 28-day cycle (n=534) or matching placebo (n=266)...
February 17, 2017: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/28212627/genome-wide-identification-of-direct-hbx-genomic-targets
#4
Francesca Guerrieri, Laura Belloni, Daniel D'Andrea, Natalia Pediconi, Loredana Le Pera, Barbara Testoni, Cecilia Scisciani, Oceane Floriot, Fabien Zoulim, Anna Tramontano, Massimo Levrero
BACKGROUND: The Hepatitis B Virus (HBV) HBx regulatory protein is required for HBV replication and involved in HBV-related carcinogenesis. HBx interacts with chromatin modifying enzymes and transcription factors to modulate histone post-translational modifications and to regulate viral cccDNA transcription and cellular gene expression. Aiming to identify genes and non-coding RNAs (ncRNAs) directly targeted by HBx, we performed a chromatin immunoprecipitation sequencing (ChIP-Seq) to analyse HBV recruitment on host cell chromatin in cells replicating HBV...
February 17, 2017: BMC Genomics
https://www.readbyqxmd.com/read/28212603/effects-of-renal-denervation-on-cardiac-oxidative-stress-and-local-activity-of-the-sympathetic-nervous-system-and-renin-angiotensin-system-in-acute-myocardial-infracted-dogs
#5
Qiaoli Feng, Chengzhi Lu, Li Wang, Lijun Song, Chao Li, Ravi Chandra Uppada
BACKGROUND: This study sought to evaluate the therapeutic effects of renal denervation (RDN) on acute myocardial infarction (MI) in canines and explore its possible mechanisms of action. METHODS: Eighteen healthy mongrel dogs were randomly assigned to either the control group, the MI group or the MI + RDN group. To assess cardiac function, left ventricular ejection fraction (LVEF), left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD) and fraction shortening (FS) were recorded...
February 17, 2017: BMC Cardiovascular Disorders
https://www.readbyqxmd.com/read/28211980/constitutional-bone-impairment-in-noonan-syndrome
#6
Giuseppina Baldassarre, Alessandro Mussa, Diana Carli, Cristina Molinatto, Giovanni Battista Ferrero
Noonan syndrome (NS) is an autosomal dominant trait characterized by genotypic and phenotypic variability. It belongs to the Ras/MAPK pathway disorders collectively named Rasopathies or neurocardiofaciocutaneous syndromes. Phenotype is characterized by short stature, congenital heart defects, facial dysmorphisms, skeletal and ectodermal anomalies, cryptorchidism, mild to moderate developmental delay/learning disability, and tumor predisposition. Short stature and skeletal dysmorphisms are almost constant and several studies hypothesized a role for the RAS pathway in regulating bone metabolism...
March 2017: American Journal of Medical Genetics. Part A
https://www.readbyqxmd.com/read/28210225/increased-apoptosis-in-the-paraventricular-nucleus-mediated-by-at1r-ras-erk1-2-signaling-results-in-sympathetic-hyperactivity-and-renovascular-hypertension-in-rats-after-kidney-injury
#7
Hongguo Zhu, Lishan Tan, Yumin Li, Jiawen Li, Minzi Qiu, Lanying Li, Mengbi Zhang, Min Liang, Aiqing Li
Background: The central nervous system plays a vital role in the development of hypertension, but the molecular regulatory mechanisms are not fully understood. This study aimed to explore signaling in the paraventricular nucleus (PVN) which might contribute to renal hypertension. Methods: Renal hypertension model was established by five-sixth nephrectomy operation (5/6Nx) in male Sprague Dawley rats. Ten weeks afterwards, they were random assigned to no treatment, or intracerebroventricular injection (ICV) with artificial cerebrospinal fluid, losartan [angiotensin II receptor type 1 (AT1R) antagonist], farnesylthiosalicylic acid (Ras inhibitor), PD98059 (MEK inhibitor), or SB203580 (p38 inhibitor) and Z-DEVD-FMK (caspase-3 inhibitor)...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28209717/autophagy-metabolism-and-cancer
#8
Jessie Yanxiang Guo, Eileen White
Macroautophagy (autophagy hereafter) is a process that collects cytoplasmic components, particularly mitochondria, and degrades them in lysosomes. In mammalian systems, basal autophagy levels are normally low but are profoundly stimulated by starvation and essential for survival. Cancer cells up-regulate autophagy and can be more autophagy-dependent than most normal tissues. Genetic deficiency in essential autophagy genes in tumors in many autochthonous mouse models for cancer reduces tumor growth. In K-ras(G12D)-driven non-small cell lung cancer (NSCLC) and other models, autophagy sustains metabolism and survival...
February 16, 2017: Cold Spring Harbor Symposia on Quantitative Biology
https://www.readbyqxmd.com/read/28209222/roles-of-angiotensin-peptides-and-recombinant-human-ace2-in-heart-failure
#9
Ratnadeep Basu, Marko Poglitsch, Haran Yogasundaram, Jissy Thomas, Brian H Rowe, Gavin Y Oudit
BACKGROUND: The renin-angiotensin system (RAS) is activated in heart failure (HF) and inhibition of RAS is a mainstay therapy for HF. Angiotensin-converting enzyme 2 (ACE2) and its product, angiotensin 1-7 (Ang-[1-7]), are important negative regulators of the RAS. OBJECTIVES: A comprehensive examination of angiotensin peptide levels and therapeutic effects of recombinant human ACE2 (rhACE2) on peptide metabolism was evaluated in human plasma and explanted heart tissue from patients with HF...
February 21, 2017: Journal of the American College of Cardiology
https://www.readbyqxmd.com/read/28207521/quantitative-assessment-of-the-relationship-between-rassf1a-gene-promoter-methylation-and-bladder-cancer-prisma
#10
Leyun Zhan, Bingyi Zhang, Yaojun Tan, Chengliang Yang, Chenhong Huang, Qiongya Wu, Yulin Zhang, Xiaobo Chen, Mi Zhou, Aihua Shu
BACKGROUND: Methylation of the Ras-association domain family 1 isoform A (RASSF1A) gene promoter region is thought to participate in the initiation and development of many different cancers. However, in bladder cancer the role of RASSF1A methylation was unclear. To evaluate the relationship between RASSF1A methylation and bladder cancer, a quantitative assessment of an independent meta-analysis was performed. In addition, a DNA methylation microarray database from the cancer genome atlas (TCGA) project was used to validate the results of the meta-analysis...
February 2017: Medicine (Baltimore)
https://www.readbyqxmd.com/read/28207424/skeletal-muscle-wasting-new-role-of-nonclassical-renin-angiotensin-system
#11
Claudio Cabello-Verrugio, Juan C Rivera, Dominga Garcia
PURPOSE OF REVIEW: Skeletal muscle can be affected by many physiological and pathological conditions that contribute to the development of muscle weakness, including skeletal muscle loss, inflammatory processes, or fibrosis. Therefore, research into therapeutic treatment alternatives or alleviation of these effects on skeletal muscle is of great importance. RECENT FINDINGS: Recent studies have shown that angiotensin (1-7) [Ang-(1-7)] - a vasoactive peptide of the nonclassical axis in the renin-angiotensin system (RAS) - and its Mas receptor are expressed in skeletal muscle...
February 16, 2017: Current Opinion in Clinical Nutrition and Metabolic Care
https://www.readbyqxmd.com/read/28205588/hypoxia-induced-angiotensin-ii-by-the-lactate-chymase-dependent-mechanism-mediates-radioresistance-of-hypoxic-tumor-cells
#12
Guozhu Xie, Ying Liu, Qiwei Yao, Rong Zheng, Lanfang Zhang, Jie Lin, Zhaoze Guo, Shasha Du, Chen Ren, Quan Yuan, Yawei Yuan
The renin-angiotensin system (RAS) is a principal determinant of arterial blood pressure and fluid and electrolyte balance. RAS component dysregulation was recently found in some malignancies and correlated with poor patient outcomes. However, the exact mechanism of local RAS activation in tumors is still unclear. Here, we find that the local angiotensin II predominantly exists in the hypoxic regions of tumor formed by nasopharyngeal carcinoma CNE2 cells and breast cancer MDA-MB-231 cells, where these tumor cells autocrinely produce angiotensin II by a chymase-dependent rather than an angiotensin converting enzyme-dependent mechanism...
February 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28204974/lipid-peroxidation-dependent-cell-death-regulated-by-gpx4-and-ferroptosis
#13
Hirotaka Imai, Masaki Matsuoka, Takeshi Kumagai, Taro Sakamoto, Tomoko Koumura
Glutathione peroxidase 4 (Phospholipid hydroperoxide glutathione peroxidase, PHGPx) can directly reduce phospholipid hydroperoxide. Depletion of GPx4 induces lipid peroxidation-dependent cell death in embryo, testis, brain, liver, heart, and photoreceptor cells of mice. Administration of vitamin E in tissue specific GPx4 KO mice restored tissue damage in testis, liver, and heart. These results indicate that suppression of phospholipid peroxidation is essential for cell survival in normal tissues in mice. Ferroptosis is an iron-dependent non-apoptotic cell death that can elicited by pharmacological inhibiting the cystine/glutamate antiporter, system Xc(-) (type I) or directly binding and loss of activity of GPx4 (Type II) in cancer cells with high level RAS-RAF-MEK pathway activity or p53 expression, but not in normal cells...
February 16, 2017: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/28204966/inhibition-of-the-renin-angiotensin-system-post-myocardial-infarction-prevents-inflammation-associated-acute-cardiac-rupture
#14
Xiao-Ming Gao, Alan Tsai, Annas Al-Sharea, Yidan Su, Shirley Moore, Li-Ping Han, Helen Kiriazis, Anthony M Dart, Andrew J Murphy, Xiao-Jun Du
PURPOSE: Inhibition of the renin-angiotensin system (RAS) is beneficial in patient management after myocardial infarction (MI). However, whether RAS inhibition also provides cardiac protection in the acute phase of MI is unclear. METHODS: Male 129sv mice underwent coronary artery occlusion to induce MI, followed by treatment with losartan (L, 20 and 60 mg/kg), perindopril (P, 2 and 6 mg/kg), amlodipine (20 mg/kg as a BP-lowering agent) or vehicle as control. Drug effects on hemodynamics were examined...
February 15, 2017: Cardiovascular Drugs and Therapy
https://www.readbyqxmd.com/read/28204818/reactive-oxygen-species-mediate-angiotensin-ii-induced-transcytosis-of-low-density-lipoprotein-across-endothelial-cells
#15
Fang Bian, Jun Cui, Tao Zheng, Si Jin
The retention of plasma low-density lipoprotein (LDL) particles to subendothelial spaces through transcytosis across the endothelium is the initial step of atherosclerosis (AS). Angiotensin II (Ang II), as the principal effector molecule of the renin-angiotensin system (RAS), is implicated in several important steps of AS development. However, whether or not Ang II can directly exert a pro‑atherogenic effect by promoting LDL transcytosis across endothelial barriers, has not been defined. In the present study, we found that Ang II upregulated intracellular reactive oxygen species (ROS) levels in endothelial cells (ECs) by measuring fluorescence of 2',7'-dichlorofluorescein (DCF‑DA)...
February 13, 2017: International Journal of Molecular Medicine
https://www.readbyqxmd.com/read/28203147/astrocyte-dependent-slow-inward-currents-sics-participate-in-neuromodulatory-mechanisms-in-the-pedunculopontine-nucleus-ppn
#16
Adrienn Kovács, Balázs Pál
Slow inward currents (SICs) are known as excitatory events of neurons caused by astrocytic glutamate release and consequential activation of neuronal extrasynaptic NMDA receptors. In the present article we investigate the role of these astrocyte-dependent excitatory events on a cholinergic nucleus of the reticular activating system (RAS), the pedunculopontine nucleus (PPN). It is well known about this and other elements of the RAS, that they do not only give rise to neuromodulatory innervation of several areas, but also targets neuromodulatory actions from other members of the RAS or factors providing the homeostatic drive for sleep...
2017: Frontiers in Cellular Neuroscience
https://www.readbyqxmd.com/read/28202657/deciphering-the-ras-erk-pathway-in-vivo
#17
REVIEW
Coralie Dorard, Georg Vucak, Manuela Baccarini
The RAS/ERK pathway has been intensely studied for about three decades, not least because of its role in human pathologies. ERK activation is observed in the majority of human cancers; in about one-third of them, it is driven by mutational activation of pathway components. The pathway is arguably one of the best targets for molecule-based pharmacological intervention, and several small-molecule inhibitors are in clinical use. Genetically engineered mouse models have greatly contributed to our understanding of signaling pathways in development, tissue homeostasis, and disease...
February 8, 2017: Biochemical Society Transactions
https://www.readbyqxmd.com/read/28202525/oncogenic-effects-of-high-mapk-activity-in-colorectal-cancer-mark-progenitor-cells-and-persist-irrespective-of-ras-mutations
#18
Cristina Blaj, Eva Marina Schmidt, Sebastian Lamprecht, Heiko Hermeking, Andreas Jung, Thomas Kirchner, David Horst
About 40% of colorectal cancers have mutations in KRAS accompanied by downstream activation of MAPK signaling which promotes tumor invasion and progression. Here we report that MAPK signaling shows strong intratumoral heterogeneity and unexpectedly remains regulated in colorectal cancer irrespective of KRAS mutation status. Using primary colorectal cancer tissues, xenograft models and MAPK reporter constructs, we showed that tumor cells with high MAPK activity resided specifically at the leading tumor edge, ceased to proliferate, underwent epithelial-mesenchymal transition (EMT), and expressed markers related to colon cancer stem cells...
February 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28202516/modeling-the-genetic-regulation-of-cancer-metabolism-interplay-between-glycolysis-and-oxidative-phosphorylation
#19
Linglin Yu, Mingyang Lu, Dongya Jia, Jianpeng Ma, Eshel Ben-Jacob, Herbert Levine, Benny A Kaipparettu, Jose' N Onuchic
Abnormal metabolism is a hallmark of cancer, yet its regulation remains poorly understood. Cancer cells were considered to utilize primarily glycolysis for ATP production, referred to as the Warburg effect. However, recent evidence suggests that oxidative phosphorylation (OXPHOS) plays a crucial role during cancer progression. Here we utilized a systems biology approach to decipher the regulatory principle of glycolysis and OXPHOS. Integrating information from literature, we constructed a regulatory network of genes and metabolites from which we extracted a core circuit containing HIF-1, AMPK, and ROS...
February 15, 2017: Cancer Research
https://www.readbyqxmd.com/read/28202167/acute-changes-in-glomerular-filtration-rate-with-renin-angiotensin-system-ras-inhibition-clinical-implications
#20
Matthew R Weir
Renin-angiotensin system inhibition with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers has been shown to be effective in reducing progression of renal and cardiovascular disease. However, these medications are often associated with an initial reduction of estimated glomerular filtration rate, which is thought to be functional but may be of clinical significance. Newer insights from secondary analyses of large clinical trials may provide important clinical perspective.
March 2017: Kidney International
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