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  • 1
    ISSN: 1432-2099
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Physics
    Notes: Abstract The spatial distribution of DNA double-strand breaks (DSB) was assessed after treatment of mammalian cells (V79) with densely ionizing radiation. Cells were exposed to beams of heavy charged particles (calcium ions: 6.9 MeV/u, 2.1⋅103 keV/μm; uranium ions: 9.0 MeV/u, 1.4⋅104 keV/μm) at the linear accelerator UNILAC of GSI, Darmstadt. DNA was isolated in agarose plugs and subjected to pulsed-field gel electrophoresis under conditions that separated DNA fragments of size 50 kbp to 5 Mbp. The measured fragment distributions were compared to those obtained after γ-irradiation and were analyzed by means of a convolution and a deconvolution technique. In contrast to the finding for γ-radiation, the distributions produced by heavy ions do not correspond to the random breakage model. Their marked overdispersion and the observed excess of short fragments reflect spatial clustering of DSB that extends over large regions of the DNA, up to several mega base pairs (Mbp). At fluences of 0.75 and 1.5/μm2, calcium ions produce nearly the same shape of fragment spectrum, merely with a difference in the amount of DNA entering the gel; this suggests that the DNA is fragmented by individual calcium ions. At a fluence of 0.8/μm2 uranium ions produce a profile that is shifted to smaller fragment sizes in comparison to the profile obtained at a fluence of 0.4/μm2; this suggests cumulative action of two separate ions in the formation of fragments. These observations are not consistent with the expectation that the uranium ions, with their much larger LET, should be more likely to produce single particle action than the calcium ions. However, a consideration of the greater lateral extension of the tracks of the faster uranium ions explains the observed differences; it suggests that the DNA is closely coiled so that even DNA locations several Mbp apart are usually not separated by less than 0.1 or 0.2 μm.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1434-3916
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Zusammenfassung Als Simulatormodell wurde am Kaninchenknie mit menschlichem IgG-Komplex eine Immun-Arthritis ausgelöst. Die verstärkte Einwanderung großmolekularer Eiweißsubstanzen konnte nach125J-Markierung von Plasmoproteinen an mit PAG-Elektrophorese aufgetrennter und autoradiographisch untersuchter Synovia nachgewiesen werden. Am synovektomierten Kaninchenknie erscheint dieser Effekt im Vergleich zur nichtoperierten Gegenseite vermindert. Mit zunehmender Anzahl postoperativer arthritischer Reize (Boosterung) scheint diese protektive Wirkung verloren zu gehen. Die Fibrose und verminderte Vaskularisierung des synovektomierten im Vergleich zum arthritischen Kniegelenk, sowie entfernte Entzündungszellen mit Entzündungsmediatoren bieten sich als morphologisches Substrat an.
    Notes: Summary An inflammatory arthritis was induced in rabbit knees by intra-articular injection of human IgG complex in immunized animals. A increased invasion of large plasma proteins into the arthritic knee could be measured by electrophoretic separation of synovial extract and autoradiographic detection of125I-labeled proteins. Synovectomy resulted in a reduced invasion of plasma proteins compared with the preoperatively arthritic knees. This protective effect was lost, however, following repeated intra-articular IgG injections. Fibrosis and decreased vascularization of the synovectomized knee, the excision of inflammatory cells, and mediators of inflammation are discussed as possible explanations.
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Woodbury, NY : American Institute of Physics (AIP)
    Applied Physics Letters 66 (1995), S. 1243-1245 
    ISSN: 1077-3118
    Source: AIP Digital Archive
    Topics: Physics
    Notes: Successful growth of silicon in a liquid phase epitaxial (LPE) system requires preventing the formation of a native oxide more than a few monolayers thick. It has been found that the desorption of oxygen and water vapor from the ends of the furnace tube can lead to oxidation of silicon wafers located in the tube center, thus inhibiting epitaxy. A simple method to avoid this problem and eliminate the need for long flush times is described. Evidence is presented that indium, a common solvent in LPE of silicon, plays a catalytic role in the oxidation of silicon. © 1995 American Institute of Physics.
    Type of Medium: Electronic Resource
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  • 4
  • 5
    Keywords: APOPTOSIS ; CANCER ; PATHWAY ; GROWTH-FACTOR RECEPTOR ; resistance ; microenvironment ; RADIORESISTANCE ; EGFRVIII ; MALIGNANT MAMMARY ; AKT ACTIVATION
    Abstract: Head and neck squamous cell carcinoma (HNSCC) is frequently characterized by high resistance to radiotherapy, which critically depends on both altered signaling pathways within tumor cells and their dynamic interaction with the tumor microenvironment. This study evaluated the prognostic value of the phosphorylation status of AKT on Ser473 and Thr308 for the clinical outcome of patients with advanced HNSCC on radiotherapy. Furthermore, we investigated the impact of AKT(Ser473) phosphorylation [p-AKT(Ser473)] in the context of radioresistance using ex vivo tissue cultures that resemble the complex tissue architecture and paracrine interaction with the tumor microenvironment. In a cohort of 120 patients with advanced HNSCC, who were treated with primary or adjuvant radiotherapy, a significant association was found between relative p-AKT(Ser473) levels and overall survival (p=0.006) as well as progression-free survival (p=0.021), while no significant correlation was revealed for relative p-AKT(Thr308) levels. In ex vivo tissue cultures p-AKT(Ser473) levels were increased upon irradiation and treatment with the PI3K inhibitor LY294002 inhibited both basal and irradiation induced AKT(Ser473) phosphorylation. Strikingly, pretreatment with LY294002 sensitized tissue cultures derived from primary and recurrent tumors to radiotherapy as determined by impaired tumor cell proliferation and enhanced DNA damage. In conclusion, phosphorylation status of AKT(Ser473) in tumor specimens serves as a novel biomarker to identify patients with advanced HNSCC at high risk for treatment failure following radiotherapy, and our data from ex vivo tissue cultures support the assumption that pharmacological inhibition of AKT(Ser473) phosphorylation might circumvent radioresistance to improve efficiency and reduce toxicity of current treatment modalities. What's new? Patients with head and neck squamous cell cancers often develop resistance to radiotherapy. To figure out how, these authors investigated AKT phosphorylation in the tumor cells. AKT kinase boosts cell proliferation when it is activated by phosphorylation at two possible sites. Could the location of phosphorylation predict whether the tumor will develop resistance? These results suggest it could. The authors show that patients with more phosphorylation at serine 473 had worse survival; furthermore, they showed that reducing phosphorylation at this site increased cancer cells' vulnerability to irradiation. Phosphorylation at the other site, threonine 308, did not affect survival.
    Type of Publication: Journal article published
    PubMed ID: 25388642
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  • 6
    Publication Date: 2018-09-18
    Description: Obesity and diabetes modulate macrophage activation, often leading to prolonged inflammation and dysfunctional tissue repair. Increasing evidence suggests that the NLRP3 inflammasome plays an important role in obesity-associated inflammation. We have previously shown that activation of the lipotoxic inflammasome by excess fatty acids in macrophages occurs via a lysosome-dependent pathway. However, the mechanisms that link cellular lipid metabolism to altered inflammation remain poorly understood. PPAR is a nuclear receptor transcription factor expressed by macrophages that is known to alter lipid handling, mitochondrial function, and inflammatory cytokine expression. To undercover novel links between metabolic signaling and lipotoxic inflammasome activation, we investigated mouse primary macrophages deficient in PPAR. Contrary to our expectation, PPAR knockout (KO) macrophages released significantly less IL-1β and IL-1α in response to lipotoxic stimulation. The suppression occurred at the transcriptional level and was apparent for multiple activators of the NLRP3 inflammasome. RNA sequencing revealed upregulation of IFN-β in activated PPARKO macrophages, and this was confirmed at the protein level. A blocking Ab against the type 1 IFNR restored the release of IL-1β to wild type levels in PPARKO cells, confirming the mechanistic link between these events. Conversely, PPAR activation with rosiglitazone selectively suppressed IFN-β expression in activated macrophages. Loss of PPAR also resulted in diminished expression of genes involved in sterol biosynthesis, a pathway known to influence IFN production. Together, these findings demonstrate a cross-talk pathway that influences the interplay between metabolism and inflammation in macrophages.
    Print ISSN: 0022-1767
    Electronic ISSN: 1550-6606
    Topics: Medicine
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