Schlagwort: cell
Discovery of mechanics of drug targets for COVID-19
A global assessment of cancer genomic alterations in epigenetic mechanisms
Muhammad A Shah, Emily L Denton, Cheryl H Arrowsmith, Mathieu Lupien and Matthieu Schapira
Abstract
Background
The notion that epigenetic mechanisms may be central to cancer initiation and progression is supported by recent next-generation sequencing efforts revealing that genes involved in chromatin-mediated signaling are recurrently mutated in cancer patients.
Results
Here, we analyze mutational and transcriptional profiles from TCGA and the ICGC across a collection 441 chromatin factors and histones. Chromatin factors essential for rapid replication are frequently overexpressed, and those that maintain genome stability frequently mutated. We identify novel mutation hotspots such as K36M in histone H3.1, and uncover a general trend in which transcriptional profiles and somatic mutations in tumor samples favor increased transcriptionally repressive histone methylation, and defective chromatin remodeling.
Conclusions
This unbiased approach confirms previously published data, uncovers novel cancer-associated aberrations targeting epigenetic mechanisms, and justifies continued monitoring of chromatin-related alterations as a class, as more cancer types and distinct cancer stages are represented in cancer genomics data repositories.
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Mitochondria and the evolutionary roots of cancer
Cancer is a group of almost 200 diseases that involve variety of changes in cell structure, morphology, and physiology. Cancer phenotype is underlying several alterations in cellular dynamics with three most critical features, which includes self-sufficiency in growth signals and insensitivity to inhibitory signals, evasion of programmed cell death and limitless replicative potential with a potential for the invasion of other organs. Cancer disease is widespread among metazoans. Some properties of cancer cells such as uncontrolled cell proliferation, lack of apoptosis, hypoxia, fermentative metabolism and free cell motility, i.e. metastasis, resemble a prokaryotic lifestyle, which leads to the assumption of a reversal like evolution from eucariotic back to proteobacterial state. This phenotype matches the phenotype of the last universal common ancestor (LUCA) that resulted from the endosymbiosis between archaebacteria and α-proteobacteria, which later became the mitochondria.
About metabolism of a carcinoma cell
Most cancer cells utilize aerobic glycolysis irrespective of their tissue of origin. The alteration from oxidative phosphorylation to glycolysis – called the Warburg effect – is an universal phenomen and has now become a diagnostic tool for cancer detection.
Variation in cancer risk among tissues can be explained by the number of stem cell divisions
Tomasetti and Vogelstein show that the lifetime risk of cancers of many different types is strongly correlated with the total number of divisions of the normal self-renewing cells maintaining that tissue’s homeostasis. These results suggest that only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions. The majority is due to bad luck, that is, random mutations arising during DNA replication in normal, noncancerous stem cells.
Implications of quantum metabolism and natural selection for the origin of cancer cells and tumor progression
Energy transfer in material solids is driven primarily by differences in intensive thermodynamic quantities such as pressure and temperature. The crucial observation in quantum-theoretical models was the consideration of the heat capacity as associated with the vibrations of atoms in a crystalline solid. However, living organisms are essentially isothermal. Because of very little differences in temperature between different parts of a cell it is assumed that energy flow in living organisms is mediated by differences in the turnover time of various metabolic processes in the cell, which occur in cyclical fashion. It has been shown that the cycle time of these metabolic processes is related to the metabolic rate, that is the rate at which the organism transforms the free energy of whatever source into metabolic work, maintenance of constant temperature and structuraland functional organization of the cells. Quantum Metabolism exploits the methodology of the quantum theory of solids to provide a molecular level which derives new rules relating metabolic rate and body size.
Einstein A (1920), Schallausbreitung in teilweise dissozieirten Gasen
Einstein A (1924) Quantentheorie des einatomigen, idealen Gases
Wholeness and implicate order: “Deep” quantum chemistry and cell consciousness: quantum chemistry controls genes and biochemistry to give cells and higher organism’s consciousness and complex behavior
Bohm used the term ‘holomovement’ which is an unbroken and undivided totality and carries an implicate order which is he totality of an order including both the manifested and non-manifested aspects of the order. Non-local quantum phenomena reside in a subtler level than quantum level that is the quantum potential which sustains intimately within the underlying implicates order and the quantum processes are driven by information from quantum potential. A global quantum field of a cell, which can be described as a super orbital, provides many levels of interactions among all particles of a cell. From quantum metabolism pint of view all electrons that are contained in one system are inseparable from eachother. In a cell the cytoplasm is a gel made of up to 30% proteins, and the structure of this gel is very much like a liquid crystal which provides collective properties of the electrons.
All these electrons within this super orbital of molecules and co-enzymes of the cell, including all the many small molecules embedded in these large biomolecules, and cofactors transporting electrons are making up one huge structure that is a global cell orbital.
Bohm D (1980) Wholeness and implicate order. Routledge Classics Eds., London and New York 191-247.
A new theory of the origin of cancer: quantum coherent entanglement, centrioles, mitosis, and differentiation
Low non-specific, low intensity laser illumination (635, 670 or 830 nm) apparently enhances centriole replication and promotes cell division, what is the opposite of a desired cancer therapy. In the contrary, centrioles are sensitive to coherent light. Then higher intensity laser illumination – still below heating threshold – may selectively target centrioles, impair mitosis and be a beneficial therapy against malignancy. If centrioles utilize quantum photons for entanglement, properties of centrosomes/centrioles approached more specifically could be useful for therapy. Healthy centrioles for a given organism or tissue differentiation should then have specific quantum optical properties detectable through some type of readout technology. An afflicted patient’s normal cells could be examined to determine the required centriole properties which may then be used to generate identical quantum coherent photons administered to the malignancy. In this mode the idea would not be to destroy the tumor – relatively low energy lasers would be used – but to “reprogram” or redifferentiate the centrioles and transform the tumor back to healthy well differentiated tissue.
Three-dimensional super-resolution microscopy of the inactive X chromosome territory reveals a collapse of its active nuclear compartment harboring distinct Xist RNA foci
Abstract
Background
A Xist RNA decorated Barr body is the structural hallmark of the compacted inactive X territory in female mammals. Using super-resolution three-dimensional structured illumination microscopy (3D-SIM) and quantitative image analysis, we compared its ultrastructure with active chromosome territories (CTs) in human and mouse somatic cells, and explored the spatio-temporal process of Barr body formation at onset of inactivation in early differentiating mouse embryonic stem cells (ESCs).
Results
We demonstrate that all CTs are composed of structurally linked chromatin domain clusters (CDCs). In active CTs the periphery of CDCs harbors low-density chromatin enriched with transcriptionally competent markers, called the perichromatin region (PR). The PR borders on a contiguous channel system, the interchromatin compartment (IC), which starts at nuclear pores and pervades CTs. We propose that the PR and macromolecular complexes in IC channels together form the transcriptionally permissive active nuclear compartment (ANC). The Barr body differs from active CTs by a partially collapsed ANC with CDCs coming significantly closer together, although a rudimentary IC channel system connected to nuclear pores is maintained. Distinct Xist RNA foci, closely adjacent to the nuclear matrix scaffold attachment factor-A (SAF-A) localize throughout Xi along the rudimentary ANC. In early differentiating ESCs initial Xist RNA spreading precedes Barr body formation, which occurs concurrent with the subsequent exclusion of RNA polymerase II (RNAP II). Induction of a transgenic autosomal Xist RNA in a male ESC triggers the formation of an ‘autosomal Barr body’ with less compacted chromatin and incomplete RNAP II exclusion.
Conclusions
3D-SIM provides experimental evidence for profound differences between the functional architecture of transcriptionally active CTs and the Barr body. Basic structural features of CT organization such as CDCs and IC channels are however still recognized, arguing against a uniform compaction of the Barr body at the nucleosome level. The localization of distinct Xist RNA foci at boundaries of the rudimentary ANC may be considered as snap-shots of a dynamic interaction with silenced genes. Enrichment of SAF-A within Xi territories and its close spatial association with Xist RNA suggests their cooperative function for structural organization of Xi.
The carcinogenic effect of various multi-walled carbon nanotubes (MWCNTs) after intraperitoneal injection in rats
Rittinghausen et al. Particle and Fibre Toxicology 2014 11:59 doi:10.1186/s12989-014-0059-z
Abstract
Background
Biological effects of tailor-made multi-walled carbon nanotubes (MWCNTs) without functionalization were investigated in vivo in a two-year carcinogenicity study. In the past, intraperitoneal carcinogenicity studies in rats using biopersistent granular dusts had always been negative, whereas a number of such studies with different asbestos fibers had shown tumor induction. The aim of this study was to identify possible carcinogenic effects of MWCNTs. We compared induced tumors with asbestos-induced mesotheliomas and evaluated their relevance for humans by immunohistochemical methods.
Methods
A total of 500 male Wistar rats (50 per group) were treated once by intraperitoneal injection with 109 or 5 × 109 WHO carbon nanotubes of one of four different MWCNTs suspended in artificial lung medium, which was also used as negative control. Amosite asbestos (108 WHO fibers) served as positive control. Morbid rats were sacrificed and necropsy comprising all organs was performed. Histopathological classification of tumors and, additionally, immunohistochemistry were conducted for podoplanin, pan-cytokeratin, and vimentin to compare induced tumors with malignant mesotheliomas occurring in humans.
Results
Treatments induced tumors in all dose groups, but incidences and times to tumor differed between groups. Most tumors were histologically and immunohistochemically classified as malignant mesotheliomas, revealing a predominantly superficial spread on the serosal surface of the abdominal cavity. Furthermore, most tumors showed invasion of peritoneal organs, especially the diaphragm. All tested MWCNT types caused mesotheliomas. We observed highest frequencies and earliest appearances after treatment with the rather straight MWCNT types A and B. In the MWCNT C groups, first appearances of morbid mesothelioma-bearing rats were only slightly later. Later during the two-year study, we found mesotheliomas also in rats treated with MWCNT D – the most curved type of nanotubes. Malignant mesotheliomas induced by intraperitoneal injection of different MWCNTs and of asbestos were histopathologically and immunohistochemically similar, also compared with mesotheliomas in man, suggesting similar pathogenesis.
Conclusion
We showed a carcinogenic effect for all tested MWCNTs. Besides aspect ratio, curvature seems to be an important parameter influencing the carcinogenicity of MWCNTs.