scholarly journals The Ins and Outs of RAS Effector Complexes

2021 ◽  
Author(s):  
Christina Kiel ◽  
David Matallanas ◽  
Walter Kolch
Keyword(s):  
Computational Modeling ◽  
Large Scale ◽  
Control Cell ◽  
Ras Signaling ◽  
Oncogenic Signaling ◽  
Functional Studies ◽  
Human Cancers ◽  
Wide Range ◽  
Effector Pathways ◽  
Oncogenic Signaling Pathways

RAS oncogenes are amongst the most commonly mutated proteins in human cancers. They regulate a wide range of effector pathways that control cell proliferation, survival, differentiation, migration and metabolic status. Including aberrations in these pathways, RAS dependent signaling is altered in more than half of human cancers. Targeting mutant RAS proteins and their downstream oncogenic signaling pathways has been elusive. However, recent results comprising detailed molecular studies, large scale omics studies and computational modeling have painted a new and more comprehensive portrait of RAS signaling that helps us to understand the intricacies of RAS, how its physiological and pathophysiological functions are regulated, and how we can target them. Here, we review these efforts particularly trying to relate the detailed mechanistic studies with global functional studies. We highlight the importance of computational modeling and data integration to derive an actionable understanding of RAS signaling that will allow us to design new mechanism based therapies for RAS mutated cancers.

scholarly journals The Ins and Outs of RAS Effector Complexes

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 236
Author(s):  
Christina Kiel ◽  
David Matallanas ◽  
Walter Kolch
Keyword(s):  
Computational Modeling ◽  
Large Scale ◽  
Control Cell ◽  
Ras Signaling ◽  
Oncogenic Signaling ◽  
Functional Studies ◽  
Human Cancers ◽  
Wide Range ◽  
Effector Pathways ◽  
Oncogenic Signaling Pathways

RAS oncogenes are among the most commonly mutated proteins in human cancers. They regulate a wide range of effector pathways that control cell proliferation, survival, differentiation, migration and metabolic status. Including aberrations in these pathways, RAS-dependent signaling is altered in more than half of human cancers. Targeting mutant RAS proteins and their downstream oncogenic signaling pathways has been elusive. However, recent results comprising detailed molecular studies, large scale omics studies and computational modeling have painted a new and more comprehensive portrait of RAS signaling that helps us to understand the intricacies of RAS, how its physiological and pathophysiological functions are regulated, and how we can target them. Here, we review these efforts particularly trying to relate the detailed mechanistic studies with global functional studies. We highlight the importance of computational modeling and data integration to derive an actionable understanding of RAS signaling that will allow us to design new mechanism-based therapies for RAS mutated cancers.

scholarly journals Are the Somatic Mutation and Tissue Organization Field Theories of Carcinogenesis Incompatible?

2013 ◽  
Vol 12 ◽  
pp. CIN.S13013 ◽  
Author(s):  
Simon Rosenfeld
Keyword(s):  
Somatic Mutation ◽  
Large Scale ◽  
Control Cell ◽  
Tissue Level ◽  
Dna Mutations ◽  
Tissue Organization ◽  
Tissue Organization Field Theory ◽  
Wide Range ◽  
Carcinogenic Agents ◽  
Successful Resolution

Two drastically different approaches to understanding the forces driving carcinogenesis have crystallized through years of research. These are the somatic mutation theory (SMT) and the tissue organization field theory (TOFT). The essence of SMT is that cancer is derived from a single somatic cell that has successively accumulated multiple DNA mutations, and that those mutations occur on genes which control cell proliferation and cell cycle. Thus, according to SMT, neoplastic lesions are the results of DNA-level events. Conversely, according to TOFT, carcinogenesis is primarily a problem of tissue organization: carcinogenic agents destroy the normal tissue architecture thus disrupting cell-to-cell signaling and compromising genomic integrity. Hence, in TOFT the DNA mutations are the effect, and not the cause, of the tissue-level events. Cardinal importance of successful resolution of the TOFT versus SMT controversy dwells in the fact that, according to SMT, cancer is a unidirectional and mostly irreversible disease; whereas, according to TOFT, it is curable and reversible. In this paper, our goal is to outline a plausible scenario in which TOFT and SMT can be reconciled using the framework and concepts of the self-organized criticality (SOC), the principle proven to be extremely fruitful in a wide range of disciplines pertaining to natural phenomena, to biological communities, to large-scale social developments, to technological networks, and to many other subjects of research.

scholarly journals Relaxed initiation pausing of ribosomes drives oncogenic translation

2021 ◽  
Vol 7 (8) ◽  
pp. eabd6927
Author(s):  
Leiming Dong ◽  
Yuanhui Mao ◽  
Aidong Zhou ◽  
Xiao-Min Liu ◽  
Jun Zhou ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Translational Control ◽  
Messenger Rna ◽  
Start Codon ◽  
Ras Signaling ◽  
Oncogenic Signaling ◽  
Oncogenic Ras ◽  
Initiation Stage ◽  
Oncogenic Signaling Pathways ◽  
Quantitative Profiling

Translation is a crucial process in cancer development and progression. Many oncogenic signaling pathways target the translation initiation stage to satisfy the increased anabolic demands of cancer cells. Using quantitative profiling of initiating ribosomes, we found that ribosomal pausing at the start codon serves as a “brake” to restrain the translational output. In response to oncogenic RAS signaling, the initiation pausing relaxes and contributes to the increased translational flux. Intriguingly, messenger RNA (mRNA) m6A modification in the vicinity of start codons influences the behavior of initiating ribosomes. Under oncogenic RAS signaling, the reduced mRNA methylation leads to relaxed initiation pausing, thereby promoting malignant transformation and tumor growth. Restored initiation pausing by inhibiting m6A demethylases suppresses RAS-mediated oncogenic translation and subsequent tumorigenesis. Our findings unveil a paradigm of translational control that is co-opted by RAS mutant cancer cells to drive malignant phenotypes.

scholarly journals β-Hexachlorocyclohexane Drives Carcinogenesis in the Human Normal Bronchial Epithelium Cell Line BEAS-2B

2021 ◽  
Vol 22 (11) ◽  
pp. 5834
Author(s):  
Elisabetta Rubini ◽  
Marco Minacori ◽  
Giuliano Paglia ◽  
Fabio Altieri ◽  
Silvia Chichiarelli ◽  
...  
Keyword(s):  
Cell Line ◽  
Environmental Pollutants ◽  
Bronchial Epithelium ◽  
Oncogenic Signaling ◽  
Carcinogenic Agent ◽  
Cell Cycle Profile ◽  
Epithelium Cell ◽  
Carcinogenic Potential ◽  
Wide Range ◽  
Oncogenic Signaling Pathways

Organochlorine pesticides constitute the majority of the total environmental pollutants, and a wide range of compounds have been found to be carcinogenic to humans. Among all, growing interest has been focused on β-hexachlorocyclohexane (β-HCH), virtually the most hazardous and, at the same time, the most poorly investigated member of the hexachlorocyclohexane family. Considering the multifaceted biochemical activities of β-HCH, already established in our previous studies, the aim of this work is to assess whether β-HCH could also trigger cellular malignant transformation toward cancer development. For this purpose, experiments were performed on the human normal bronchial epithelium cell line BEAS-2B exposed to 10 µM β-HCH. The obtained results strongly support the carcinogenic potential of β-HCH, which is achieved through both non-genotoxic (activation of oncogenic signaling pathways and proliferative activity) and indirect genotoxic (ROS production and DNA damage) mechanisms that significantly affect cellular macroscopic characteristics and functions such as cell morphology, cell cycle profile, and apoptosis. Taking all these elements into account, the presented study provides important elements to further characterize β-HCH, which appears to be a full-fledged carcinogenic agent.

scholarly journals Oncogenic role of a developmentally regulated NTRK2 splice variant

2022 ◽  
Author(s):  
Siobhan S Pattwell ◽  
Sonali Arora ◽  
Nicholas Nuechterlein ◽  
Michael Zager ◽  
Keith R Loeb ◽  
...  
Keyword(s):  
Splice Variant ◽  
Affinity Purification ◽  
Neurotrophin Receptor ◽  
Oncogenic Signaling ◽  
Developmentally Regulated ◽  
Multiple Tumor ◽  
Wide Range ◽  
Tumor Types ◽  
Affinity Purification Mass Spectrometry ◽  
Oncogenic Signaling Pathways

Temporally-regulated alternative splicing choices are vital for proper development yet the wrong splice choice may be detrimental. Here we highlight a novel role for the neurotrophin receptor splice variant TrkB.T1 in neurodevelopment, embryogenesis, transformation, and oncogenesis across multiple tumor types in both humans and mice. TrkB.T1 is the predominant NTRK2 isoform across embryonic organogenesis and forced over-expression of this embryonic pattern causes multiple solid and nonsolid tumors in mice in the context of tumor suppressor loss. TrkB.T1 also emerges the predominant NTRK isoform expressed in a wide range of adult and pediatric tumors, including those harboring TRK fusions. Affinity purification-mass spectrometry (AP-MS) proteomic analysis reveals TrkB.T1 has distinct interactors with known developmental and oncogenic signaling pathways such as Wnt, TGF-β, Hedgehog, and Ras. From alterations in splicing factors to changes in gene expression, the discovery of isoform specific oncogenes with embryonic ancestry has the potential to shape the way we think about developmental systems and oncology.

Electron microscopy study of reactively sputter-deposited Ti/N films on silicon

1992 ◽  
Vol 50 (2) ◽  
pp. 1362-1363
Author(s):  
V. C. Kannan ◽  
A. K. Singh ◽  
R. B. Irwin ◽  
S. Chittipeddi ◽  
F. D. Nkansah ◽  
...  
Keyword(s):  
Integrated Circuits ◽  
Large Scale ◽  
Hexagonal Phase ◽  
Microscopy Study ◽  
Electron Microscopy Study ◽  
Process Conditions ◽  
Tin Films ◽  
Wide Range ◽  
Fcc Phase ◽  
Circuits Vlsi

Titanium nitride (TiN) films have historically been used as diffusion barrier between silicon and aluminum, as an adhesion layer for tungsten deposition and as an interconnect material etc. Recently, the role of TiN films as contact barriers in very large scale silicon integrated circuits (VLSI) has been extensively studied. TiN films have resistivities on the order of 20μ Ω-cm which is much lower than that of titanium (nearly 66μ Ω-cm). Deposited TiN films show resistivities which vary from 20 to 100μ Ω-cm depending upon the type of deposition and process conditions. TiNx is known to have a NaCl type crystal structure for a wide range of compositions. Change in color from metallic luster to gold reflects the stabilization of the TiNx (FCC) phase over the close packed Ti(N) hexagonal phase. It was found that TiN (1:1) ideal composition with the FCC (NaCl-type) structure gives the best electrical property.

THE SOME QUESTIONS OF AUTONOMOUS MOTION AND MANAGEMENT OF LAND-MOBILE ROBOTIC COMPLEXES FOR UKRAINIAN GROUND FORCESE

2019 ◽  
pp. 53-58
Author(s):  
О. Кravchuk ◽  
V. Symonenkov ◽  
I. Symonenkova ◽  
O. Hryhorev
Keyword(s):  
Large Scale ◽  
Armed Forces ◽  
Distributed Information ◽  
Wide Range ◽  
Highly Effective ◽  
Information Management Systems ◽  
Robotic Devices ◽  
Principles And Standards ◽  
And Control ◽  
The Eu

Today, more than forty countries of the world are engaged in the development of military-purpose robots. A number of unique mobile robots with a wide range of capabilities are already being used by combat and intelligence units of the Armed forces of the developed world countries to conduct battlefield intelligence and support tactical groups. At present, the issue of using the latest information technology in the field of military robotics is thoroughly investigated, and the creation of highly effective information management systems in the land-mobile robotic complexes has acquired a new phase associated with the use of distributed information and sensory systems and consists in the transition from application of separate sensors and devices to the construction of modular information subsystems, which provide the availability of various data sources and complex methods of information processing. The purpose of the article is to investigate the ways to increase the autonomy of the land-mobile robotic complexes using in a non-deterministic conditions of modern combat. Relevance of researches is connected with the necessity of creation of highly effective information and control systems in the perspective robotic means for the needs of Land Forces of Ukraine. The development of the Armed Forces of Ukraine management system based on the criteria adopted by the EU and NATO member states is one of the main directions of increasing the effectiveness of the use of forces (forces), which involves achieving the principles and standards necessary for Ukraine to become a member of the EU and NATO. The inherent features of achieving these criteria will be the transition to a reduction of tasks of the combined-arms units and the large-scale use of high-precision weapons and land remote-controlled robotic devices. According to the views of the leading specialists in the field of robotics, the automation of information subsystems and components of the land-mobile robotic complexes can increase safety, reliability, error-tolerance and the effectiveness of the use of robotic means by standardizing the necessary actions with minimal human intervention, that is, a significant increase in the autonomy of the land-mobile robotic complexes for the needs of Land Forces of Ukraine.

Stirring and aeration system for the upgrading of small waste water treatment plants

1994 ◽  
Vol 29 (12) ◽  
pp. 149-156 ◽  
Author(s):  
Marcus Höfken ◽  
Katharina Zähringer ◽  
Franz Bischof
Keyword(s):  
Waste Water ◽  
Water Treatment ◽  
Large Scale ◽  
Waste Water Treatment ◽  
Water Treatment Plants ◽  
Waste Water Treatment Plants ◽  
Basic Fluid ◽  
Aeration System ◽  
Technical Realization ◽  
Wide Range

A novel agitating system has been developed which allows for individual or combined operation of stirring and aeration processes. Basic fluid mechanical considerations led to the innovative hyperboloid design of the stirrer body, which ensures high efficiencies in the stirring and the aeration mode, gentle circulation with low shear forces, excellent controllability, and a wide range of applications. This paper presents the basic considerations which led to the operating principle, the technical realization of the system and experimental results in a large-scale plant. The characteristics of the system and the differences to other stirring and aeration systems are illustrated. Details of the technical realization are shown, which conform to the specific demands of applications in the biological treatment of waste water. Special regard is given to applications in the upgrading of small compact waste water treatment plants.

Thin structure of heterogeneous and multiphase fluid flows

2012 ◽  
Vol 9 (1) ◽  
pp. 175-180
Author(s):  
Yu.D. Chashechkin
Keyword(s):  
Large Scale ◽  
Fundamental System ◽  
Fluid Flows ◽  
Regular Solutions ◽  
Flow Models ◽  
Group Methods ◽  
Wide Range ◽  
Thin Structure ◽  
Multiphase Fluid ◽  
Complete Solutions

According to the results of visualization of streams, the existence of structures in a wide range of scales is noted: from galactic to micron. The use of a fundamental system of equations is substantiated based on the results of comparing symmetries of various flow models with the usage of theoretical group methods. Complete solutions of the system are found by the methods of the singular perturbations theory with a condition of compatibility, which determines the characteristic equation. A comparison of complete solutions with experimental data shows that regular solutions characterize large-scale components of the flow, a rich family of singular solutions describes formation of the thin media structure. Examples of calculations and observations of stratified, rotating and multiphase media are given. The requirements for the technique of an adequate experiment are discussed.

MALAT1 as a Versatile Regulator of Cancer: Overview of the updates from Predatory role as Competitive Endogenous RNA to Mechanistic In-sights

2020 ◽  
Vol 20 ◽  
Author(s):  
Ammad Ahmad Farooqi ◽  
Evangelia Legaki ◽  
Maria Gazouli ◽  
Silvia Rinaldi ◽  
Rossana Berardi
Keyword(s):  
Molecular Biology ◽  
Detailed Analysis ◽  
Signaling Pathways ◽  
Individualized Medicine ◽  
Signaling Cascades ◽  
Oncogenic Signaling ◽  
Non Coding Rnas ◽  
Oncogenic Signaling Pathways ◽  
Competitive Endogenous Rna

: Central dogma of molecular biology has remained cornerstone of classical molecular biology but serendipitous discovery of microRNAs (miRNAs) in nematodes paradigmatically shifted our current understanding of the intricate mech-anisms which occur during transitions from transcription to translation. Discovery of miRNA captured tremendous attention and appreciation and we had witnessed an explosion in the field of non-coding RNAs. Ground-breaking discoveries in the field of non-coding RNAs have helped in better characterization of microRNAs and long non-coding RNAs (LncRNAs). There is an ever-increasing list of miRNA targets which are regulated by MALAT1 to stimulate or repress expression of tar-get genes. However, in this review our main focus is to summarize mechanistic insights related to MALAT1-mediated regu-lation of oncogenic signaling pathways. We have discussed how MALAT1 modulated TGF/SMAD and Hippo pathways in various cancers. We have also comprehensively summarized how JAK/STAT and Wnt/β-catenin pathways stimulated MALAT1 expression and consequentially how MALAT1 potentiated these signaling cascades to promote cancer. MALAT1 research has undergone substantial broadening however, there is still a need to identify additional mechanisms. MALAT1 is involved in multi-layered regulation of multiple transduction cascades and detailed analysis of different pathways will be helpful in getting a step closer to individualized medicine.

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