Innovative Computertomographie verbessert Beurteilung der koronaren Herzkrankheit

Forschende der Universitätsmedizin Mainz haben gezeigt, dass eine neuartige Computertomographie (CT) mit einem sogenannten Photon-Counting-Detektor (PCD-CT) die Beurteilung der koronaren Herzerkrankung verbessern kann. Durch die ultrahochauflösende PCD-CT lassen sich Blutgefäße und Gefäßablagerungen genauer darstellen als bisher. Mit Hilfe der innovativen Diagnostikmethode konnten in der Mainzer Studie über 50 Prozent der Patient:innen in eine niedrigere Krankheitskategorie eingestuft werden. Die Technologie hat das Potenzial, die Patientenversorgung zu verbessern und Gesundheitskosten zu reduzieren.

Quelle: IDW Informationsdienst Wissenschaft

Kardio-CT als Kassenleistung: Herzstiftung begrüßt G-BA-Beschluss, Anbindung an Kardiologie-Expertise erforderlich

Aufnahme nicht-invasiver Koronarer Computertomographie-Angiographie in den Leistungskatalog der gesetzlichen Krankenkassen: „Wichtiger Schritt“ zu besserer Versorgung von Menschen mit koronarer Herzkrankheit und einem Risiko für Herzinfarkt und Herztod

Quelle: IDW Informationsdienst Wissenschaft

Herz-CT: schnell, schonend und sicher für Patientinnen und Patienten

Die koronare Herzkrankheit (KHK) ist die häufigste Todesursache in Deutschland. An den Folgen dieser Volkskrankheit sterben jährlich über 120.000 Menschen. Für ihre erfolgreiche Behandlung ist eine frühzeitige und genaue Diagnose entscheidend. Mit Beschluss des Gemeinsamen Bundesausschusses vom 18. Januar steht gesetzlich Versicherten schon bald neben der Herzkatheteruntersuchung alternativ die schonende und nicht-invasive Herz-CT oder CT-Koronarangiografie zur Verfügung. Wir stellen diese aus Anlass des Tages des Patienten am 26. Januar 2024 vor.

Quelle: IDW Informationsdienst Wissenschaft

CT-Untersuchungen bei jungen Menschen – Zusammenhang zwischen Strahlenbelastung und erhöhtem Risiko für Blutkrebs

Jährlich unterziehen sich in Europa mehr als eine Million Kinder einer Computertomographie (CT). Eine multinationale Studie unter Beteiligung des Instituts für Biometrie und Registerforschung der Medizinischen Hochschule Brandenburg Theodor Fontane (MHB) bestätigt den Zusammenhang zwischen Strahlenbelastung durch CT-Untersuchungen bei jungen Menschen und erhöhtem Risiko für Blutkrebs. Betont wird zudem die Notwendigkeit, das Bewusstsein der Ärzteschaft zu schärfen und weiterhin strenge Strahlenschutzmaßnahmen zu ergreifen.

Quelle: IDW Informationsdienst Wissenschaft

Methylierungsanalyse verbessert Lungenkrebs-Risikovorhersage

Durch gezielte CT-basierte Früherkennung in Hochrisikogruppen ließe sich die Zahl der Sterbefälle an Lungenkrebs deutlich reduzieren. Das Lungenkrebs-Risiko wird bislang üblicherweise anhand der Raucherhistorie ermittelt. Deutlich präziser kann das Risiko eingeschätzt werden, wenn zusätzlich der Methylierungsstatus bestimmter Gene untersucht wird, zeigten nun Wissenschaftlerinnen und Wissenschaftler vom Deutschen Krebsforschungszentrum (DKFZ).

Quelle: IDW Informationsdienst Wissenschaft

Künstliche Intelligenz für die Osteoporose-Diagnostik

Forschende der Uni Kiel haben eine Software entwickelt, die Wirbelbrüche auf CT-Bildern automatisch erkennt und prognostisch bewertet.

Quelle: IDW Informationsdienst Wissenschaft

Ultraschall bei Lungenembolie: Schnelle Therapieentscheidung am Krankenbett

Ultraschalluntersuchungen sind in Deutschland flächendeckend verfügbar, sie sind kostengünstig und strahlenfrei. Zudem reicht ihre Aussagekraft mittlerweile oft an die der wesentlich teureren CT- und MRT-Aufnahmen heran. Dies findet nun auch zunehmend Eingang in die medizinischen Leitlinien. Die gerade aktualisierte S2k-Leitlinie „Diagnostik und Therapie der Venenthrombose und Lungenembolie“ der Deutschen Gesellschaft für Angiologie räumt dem Ultraschall jetzt eine wichtigere Rolle ein. Die Deutsche Gesellschaft für Ultraschall in der Medizin e.V. (DEGUM) hat an der Leitlinie mitgearbeitet und begrüßt die Änderung. So könnten wichtige Therapieentscheidungen viel schneller getroffen werden.

Quelle: IDW Informationsdienst Wissenschaft

Integrating medical imaging and cancer biology with deep neural networks

Scientists have carried out a study investigating whether deep neural networks can represent associations between gene expression, histology, and CT-derived image features. They found that the network could not only reproduce previously reported associations but also identify new ones.

Quelle: Sciencedaily

Vorsprung durch Forschung

Ob Tiger im CT oder Ultraschall-Untersuchungen beim Panda – Zoo und Tierpark Berlin sind froh, die Wissenschaftler*innen des Berliner Leibniz-Instituts für Zoo- und Wildtierforschung (Leibniz-IZW) stets mit Rat und Tat an ihrer Seite zu wissen. Die enge Zusammenarbeit der Einrichtungen soll nun durch den Neubau eines Erweiterungsgebäudes des Leibniz-IZW weiter ausgebaut werden.

Quelle: IDW Informationsdienst Wissenschaft

AI system detects SARS-CoV-2 on CT scans: DFKI presents method for image-based diagnosis of Corona

Apart from the commonly used PCR tests for the diagnosis of infections with SARS-CoV-2, the Corona virus can also be detected on computed tomography scans. With a new method of automated image recognition, this form of diagnosis can be refined and made more comprehensible for medical staff. In an international cooperation, the DFKI research department Interactive Machine Learning (IML) has developed an interactive AI system that, with a success rate of 92 percent, allows for one of the most precise automatic diagnosis of SARS-CoV-2 using CT scans from a special, publicly available test data set in the world.

Quelle: IDW Informationsdienst Wissenschaft

KI-System erkennt SARS-CoV-2 auf CT-Scans: DFKI stellt Methode zur bildbasierten Diagnose von Corona vor

Neben den verbreiteten PCR-Tests zur Diagnose von Infektionen mit SARS-CoV-2 lässt sich das Coronavirus auch auf Computertomographie-Scans erkennen. Durch eine neue Methode in der automatisierten Bilderkennung kann diese Diagnoseform präzisiert und für das medizinische Personal nachvollziehbarer gemacht werden. In einer internationalen Kooperation hat der DFKI-Forschungsbereich Interaktives Maschinelles Lernen (IML) ein interaktives KI-System entwickelt, das mit einer Erfolgsrate von 92 Prozent auf einem speziellen, öffentlich verfügbaren Testdatensatz eine der weltweit präzisesten automatischen Diagnosen von SARS-CoV-2 anhand von CT-Scans ermöglicht.

Quelle: IDW Informationsdienst Wissenschaft

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.

Continue reading „A global assessment of cancer genomic alterations in epigenetic mechanisms“

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.

 Davila AF and Zamorano P (2013) Mitochondria and the evolutionary roots of cancer. Phys. Biol. 10 (2013) 026008, doi:10.1088/1478-3975/10/2/026008

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.

Warburg O, Posener K, Negelein E. (1924) Über den Stoffwechsel der Carcinomzelle. Biochem Z. 152, 309–344.

A Mitochondrial Paradigm of Metabolic and Degenerative Diseases, Aging, and Cancer: A Dawn for Evolutionary Medicine

Progressive increase in mtDNA 3243A>G heteroplasmy causes abrupt transcriptional reprogramming

Wallace hypothesized mitochondrial dysfunction as a central role in a wide range of age-related disorders and various forms of cancer. Steadily rising increases in mitochondrial DNA mutations cause abrupt shifts in diseases. Discrete changes in nuclear gene expression in response to small increases in DNA mutant level are analogous to the phase shifts that is well known in physics: As heat is added, the ice abruptly turns to water or with more heat abruptly to steam. Therefore, a quantitative change that is an increasing proportion of mitochondrial DNA mutation results in a qualitative change  which coordinate changes in nuclear gene expression together with discrete changes in clinical symptoms.

 Wallace DC (2005) A Mitochondrial Paradigm of Metabolic and Degenerative Diseases, Aging, and Cancer: A Dawn for Evolutionary Medicine. Annu Rev Genet. 2005 ; 39: 359. doi:10.1146/annurev.genet.39.110304.095751

Picard M et. Al (2014) Progressive increase in mtDNA 3243A>G heteroplasmy causes abrupt transcriptional reprogramming. PNAS E4033–E4042, doi: 10.1073/pnas.1414028111

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.

Tomasetti C, Vogelstein B (2015): Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 2 January 2015: Vol. 347 no. 6217 pp. 78-81 DOI: 10.1126/science.1260825

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.

Davies P, Lloyd A, Demetrius LA, Tuszynski, JA (2012) Implications of quantum metabolism and natural selection for the origin of cancer cells and tumor progression. Citation: AIP Advances 2, 011101 (2012); doi: 10.1063/1.3697850

Einstein A (1920), Schallausbreitung in teilweise dissozieirten Gasen

Einstein A (1924) Quantentheorie des einatomigen, idealen Gases

Quantum entanglement between the electron clouds of nucleic acids in DNA

Rieper, Anders and Vedral modelled the electron clouds of nucleic acids in a single strand of DNA as a chain of coupled quantum harmonic oscillators with dipole-dipole interaction between nearest neighbours. As a main result, the entanglement contained in the chain coincides with the binding energy of the molecule. Derived in the limit of long distances and periodic potentials analytic expressions linking the entanglement witnesses to the energy reduction due to the quantum entanglement in the electron clouds.

Rieper E, Anders J, Vedral V (2011) Quantum entanglement between the electron clouds of nucleic acids in DNA. arxiv.org/abs/1006.4053

 

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.

Ventegodt S, Hermansen TD, Flensborg-Madsen T, Nielsen ML and Merrick J (2006) A theory of “Deep” quantum chemistry and cell consciousness: quantum chemistry controls genes and biochemistry to give cells and higher organism’s consciousness and complex behavior. The Scientific World Journal 6, 1441-1453.

Quantum Tunnelling to the Origin and Evolution of Life

Quantum tunnelling is a phenomenon which becomes relevant at the nanoscale and below. It is a paradox from the classical point of view as it enables elementary particles and atoms to permeate an energetic barrier without the need for sufficient energy to overcome it. Tunnelling is being of vital importance for life: physical and chemical processes can be traced directly back to the effects of quantum tunnelling. These processes include the   prebiotic chemistry as well as the function of biomolecular nanomachines and has many highly important implications that can be derived from to the field of molecular, prebiotic chemistry and biological evolution, respectively.

Trixler, F (2013) Quantum Tunnelling to the Origin and Evolution of Life. Curr Org Chem. 2013 Aug; 17(16): 1758–1770. doi: 10.2174%2F13852728113179990083

Quantum Teleportation and Von Neumann Entropy

From the aspect of the quantum information theories, various quantum entropies are possibly computed at each stage, which ensures the emergence of the entangled states in the intermediate step. If a single qubit quantum teleportation is near the computational basis, the quantum measurement is dominantly responsible for the joint entropy at the final stage. If it is far from the computational basis, this dominant responsibility is moved into the quantum measurement of system. Therefore, the relative entropy can be regarded as a measure for distance between two different quantum states like trace distance or fidelity. Some relative entropies become infinity, which indicates the non-trivial intersection of the support of one quantum state with kernel of the other quantum state.

You Hwan Ju, Eylee Jung1, Mi-Ra Hwang, D. K. Park, Hungsoo Kim, Min-Soo Kim, Jin-Woo Son, Sahng-Kyoon Yoo, S. Tamaryan (2007) Quantum Teleportation and Von Neumann Entropy. arXiv:0707.1227v1

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.

Hameroff, SR (2004) A new theory of the origin of cancer: quantum coherent entanglement, centrioles, mitosis, and differentiation. BioSystems 77, 119–136

Three-dimensional super-resolution microscopy of the inactive X chromosome territory reveals a collapse of its active nuclear compartment harboring distinct Xist RNA foci

3D-SIM-based DAPI intensity classification in the Barr body versus the entire nucleus of C2C12 cells. (A) Mid z-section of a DAPI-stained nucleus. The area below the dashed line illustrates the resolution level obtained by wide-field deconvolution microscopy, for comparison. Inset magnifications show the non-uniformly compacted structure of the Barr body resolvable with 3D-SIM (1) and an arbitrary autosomal region with CDCs (2). Scale bars: 5 μm, insets 1 μm. (B) X chromosome-specific painting (green) of Xi (left) and Xa territories (right) of the same nucleus in different z-sections. Note the high convergence between the painted Xi and the DAPI visualized Barr body (arrowheads). Scale bars: 2 μm, insets 1 μm. (C) 3D DAPI intensity classification exemplified for the nucleus shown in (A). Seven DAPI intensity classes displayed in false-color code ranging from class 1 (blue) representing pixels close to background intensity, largely representing the IC, up to class 7 (white) representing pixels with highest density, mainly associated with chromocenters. Framed areas of the Barr body (inset 1) and a representative autosomal region (inset 2) are shown on the right at resolution levels of 3D-SIM, deconvolution and conventional wide-field microscopy. The Xi territory pervaded by lower DAPI intensities becomes evident only at 3D-SIM resolution, whereas both wide-field and deconvolution microscopy imply a concentric increase of density in the Barr body. In the autosomal region, chromatin assigned to classes 2 to 3 lines compacted CDCs, represented by classes 4 to 6. (D) Left: average DAPI intensity classification profiles with standard deviations evaluated for entire nuclear volumes or the Barr body region only (dark grey bars). Right: over/underrepresentation of the average DAPI intensity class fraction sizes in the Barr body versus entire nuclear volumes (n = 12). Distribution differences on classes between Xi and entire nucleus P <0.001. 3D-SIM, three-dimensional structured illumination microscopy; CDC, chromatin domain cluster; DAPI, 4',6-diamidino-2-phenylindole; FISH, fluorescence in situ hybridization; IC, interchromatin compartment; Xa, active X chromosome; Xi, inactive X chromosome. Smeets et al. Epigenetics & Chromatin 2014 7:8   doi:10.1186/1756-8935-7-8
3D-SIM-based DAPI intensity classification in the Barr body versus the entire nucleus of C2C12 cells. (A) Mid z-section of a DAPI-stained nucleus. The area below the dashed line illustrates the resolution level obtained by wide-field deconvolution microscopy, for comparison. Inset magnifications show the non-uniformly compacted structure of the Barr body resolvable with 3D-SIM (1) and an arbitrary autosomal region with CDCs (2). Scale bars: 5 μm, insets 1 μm. (B) X chromosome-specific painting (green) of Xi (left) and Xa territories (right) of the same nucleus in different z-sections. Note the high convergence between the painted Xi and the DAPI visualized Barr body (arrowheads). Scale bars: 2 μm, insets 1 μm. (C) 3D DAPI intensity classification exemplified for the nucleus shown in (A). Seven DAPI intensity classes displayed in false-color code ranging from class 1 (blue) representing pixels close to background intensity, largely representing the IC, up to class 7 (white) representing pixels with highest density, mainly associated with chromocenters. Framed areas of the Barr body (inset 1) and a representative autosomal region (inset 2) are shown on the right at resolution levels of 3D-SIM, deconvolution and conventional wide-field microscopy. The Xi territory pervaded by lower DAPI intensities becomes evident only at 3D-SIM resolution, whereas both wide-field and deconvolution microscopy imply a concentric increase of density in the Barr body. In the autosomal region, chromatin assigned to classes 2 to 3 lines compacted CDCs, represented by classes 4 to 6. (D) Left: average DAPI intensity classification profiles with standard deviations evaluated for entire nuclear volumes or the Barr body region only (dark grey bars). Right: over/underrepresentation of the average DAPI intensity class fraction sizes in the Barr body versus entire nuclear volumes (n = 12). Distribution differences on classes between Xi and entire nucleus P Smeets et al. Epigenetics & Chromatin 2014 7:8 doi:10.1186/1756-8935-7-8

Daniel Smeets, Yolanda Markaki, Volker J Schmid, Felix Kraus, Anna Tattermusch, Andrea Cerase, Michael Sterr, Susanne Fiedler, Justin Demmerle, Jens Popken, Heinrich Leonhardt, Neil Brockdorff, Thomas Cremer1, Lothar Schermelleh and Marion Cremer

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.

Continue reading „Three-dimensional super-resolution microscopy of the inactive X chromosome territory reveals a collapse of its active nuclear compartment harboring distinct Xist RNA foci“

The carcinogenic effect of various multi-walled carbon nanotubes (MWCNTs) after intraperitoneal injection in rats

Non-neoplastic histopathological findings in the abdominal cavity. A: High-power view of anti-podoplanin immunohistochemistry showing single MWCNT A (high dose) nanotubes in the tissue (arrows). B: High-power view of anti-podoplanin immunohistochemistry showing single asbestos fibers in the tissue (arrows). C: H & E, high-power view of granuloma induced by MWCNT A (low dose) nanotubes including single nanotube (arrow, 25×). D: H & E, high-power view of granuloma induced by asbestos including single fiber (arrow, 40×). Rittinghausen et al. Particle and Fibre Toxicology 2014 11:59   doi:10.1186/s12989-014-0059-z
Non-neoplastic histopathological findings in the abdominal cavity. A: High-power view of anti-podoplanin immunohistochemistry showing single MWCNT A (high dose) nanotubes in the tissue (arrows). B: High-power view of anti-podoplanin immunohistochemistry showing single asbestos fibers in the tissue (arrows). C: H & E, high-power view of granuloma induced by MWCNT A (low dose) nanotubes including single nanotube (arrow, 25×). D: H & E, high-power view of granuloma induced by asbestos including single fiber (arrow, 40×).
Rittinghausen et al. Particle and Fibre Toxicology 2014 11:59 doi:10.1186/s12989-014-0059-z

Susanne Rittinghausen, Anja Hackbarth, Otto Creutzenberg, Heinrich Ernst, Uwe Heinrich, Albrecht Leonhardt and Dirk Schaudien

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.

Continue reading „The carcinogenic effect of various multi-walled carbon nanotubes (MWCNTs) after intraperitoneal injection in rats“

Forscher des HIPS und des HZI finden neues Antibiotikum gegen gram-negative Bakterien

Biologinnen untersuchen Bakterien unter dem Mikroskop. Foto: Oliver Dietze
Biologinnen untersuchen Bakterien unter dem Mikroskop. Foto: Universität des Saarlandes, Oliver Dietze

Die Erreger von Infektionserkrankungen Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumanii und Pseudomonas aeruginosa haben zwei große Gemeinsamkeiten: Sie gehören zu den sogenannten gram-negativen Bakterien und sind in Krankenhäusern besonders gefürchtet. Wissenschaftler des Helmholtz-Instituts für Pharmazeutische Forschung Saarland (HIPS) und des Helmholtz-Zentrums für Infektionsforschung (HZI) in Braunschweig haben nun ein potenzielles neues Antibiotikum entdeckt, das gegen diese schwer zu bekämpfenden Bakterien wirkt. Ihre Ergebnisse veröffentlichten die Forscher im renommierten Journal Angewandte Chemie International Edition.

Immer mehr Keime entwickeln Resistenzen gegen Antibiotika, sodass diese einstigen Wunderwaffen ihre Wirkungskraft verlieren. Vor allem in Krankenhäusern stellt die steigende Anzahl resistenter Keime das Personal vor große Probleme und ist eine große Gefahr für die Patienten. „Am schwierigsten zu behandeln ist die Gruppe der gram-negativen Bakterien. Diese besitzen zwei Zellmembranen. Potenzielle Wirkstoffe müssen durch beide hindurch, um eine Wirkung zu erzielen“, sagt Prof. Rolf Müller, Geschäftsführender Direktor des HIPS. Dadurch sind die Anforderungen an mögliche Wirkstoffe wesentlich komplexer als bei den gram-positiven Bakterien, die nur eine Zellmembran besitzen.

Trotz der komplexen Anforderungen ist es Müller und seinen Kollegen aus der Abteilung „Mikrobielle Naturstoffe“ am HIPS und „Mikrobielle Wirkstoffe“ am HZI gelungen, aus dem Myxobakterium Cystobacter sp. einen Stoff zu isolieren, der auch gegen gram-negative Bakterien wirkt. „Wir haben eine aus chemischer Sicht vollkommen neue Stoffklasse entdeckt, die wir Cystobactamide getauft haben“, sagt Müller. „In Experimenten haben wir gezeigt, dass diese gegen die gram-negativen Bakterien Escherichia coli und Acinetobacter baumannii wirksam sind.“ Die Wirkstoffe sind also in der Lage, die doppelte Zellmembran zu durchdringen und die Bakterien so bekämpfen.

Auch wie sie ihre Wirkung entfalten, konnten die Wissenschaftler bereits zeigen. „Wir konnten nachweisen, dass die Cystobactamide als Gyrasehemmer fungieren: Sie verhindern, dass die DNA der Bakterien platzsparend wie ein verdrillter Gartenschlauch verdichtet werden kann“, erläutert Müller. Wird dieser Vorgang gestört, kann die DNA auch nicht mehr korrekt abgelesen werden, und der Stoffwechsel wird entscheidend behindert.

Gyrasehemmer an sich sind nichts Neues. Ganz im Gegenteil: Viele der bisherigen und wirksamsten Antibiotika basieren auf diesem Prinzip. „Allerdings konnten wir erstmals einen Wirkstoff aus Naturstoffen gewinnen, der so funktioniert“, sagt Müller. Das Potenzial der bekannten, chemisch hergestellten Gyrasehemmer ist praktisch ausgeschöpft. Sie können nach jahrzehntelanger Verbesserung nicht weiterentwickelt werden. In der neuen Stoffklasse der Cystobactamide hingegen gibt es noch vielfältige Optimierungsmöglichkeiten. „Wir hoffen, durch chemische Veränderungen vor allem die Wirkung gegen gram-negative Bakterien weiter verstärken und verbreitern zu können“, erklärt Müller. „Sollte uns das gelingen, sind Cystobactamide ein echter Hoffnungsträger im Kampf gegen Krankenhauskeime und andere gram-negative Bakterien.“

Originalpublikation in Angewandte Chemie International Edition:

Baumann, S., Herrmann, J., Raju, R., Steinmetz, H., Mohr, K. I.,
Hüttel, S., Harmrolfs, K., Stadler, M. and Müller, R. (2014):
„Cystobactamids: Myxobacterial Topoisomerase Inhibitors Exhibiting
Potent Antibacterial Activity“. DOI: 10.1002/anie.201409964
<http://onlinelibrary.wiley.com/doi/10.1002/anie.201409964/full>