Hydrogeologische/Hydrologische Untersuchung einer Prä-Flutungssituation am Beispiel des Gessentals im ehemaligen ostthüringischen Uranbergbaugebiet

Zur Aufnahme und Beschreibung der Prozesse und der Dynamik des bergbauinduzierten Stoffeintrags und -austrags aus einer Uranbergbauhalde während einer Prä-Flutungssituation in ein z.T. entwässertes Talsystem wurden im 30 km² großen Einzugsgebiet des Gessenbaches (Gessental) zwischen 1997 und 2001 hydrologische/hydrogeologische Feld- und Laborarbeiten sowie hydrochemische Modellierungen durchgeführt. Neben den sedimentologischen, geophysikalischen und hydrogeologischen zeigen die hydrogeochemischen prozessorientierten Untersuchungen dieser Arbeit eine Möglichkeit, die Signatur einer definierten Schadstoffquelle über die Vorflut und die Talsedimente zu verfolgen. Das in ein System ohne hydraulische Ankopplung an das hydrogeologische Regime eintretende Haldensickerwasser führt zur Ausbildung von temporären vermutlich metastabilen geochemischen Barrieren , welche den Transport und den Austrag von Schadstoffen verzögern kann. Systeme mit hydraulischer Ankopplung an das Grundwasser weisen eine höhere Transferwirkung auf. Modifikationen der hydrogeologischen Randbedingungen durch die zukünftig austretenden Flutungswässer des Uranbergbaus werden zu einer Veränderung der geochemischen Ausgangsbedingungen führen und die Transferwirkung vermutlich erhöhen. Die Untersuchungen liefern die Eingangsdaten für zukünftige Analysen und Grundwassermodellierungen des Post-Flutungszeitraumes im Gessental bei Ronneburg

Improved Killing of Human High-Grade Glioma Cells by Combining Ionizing Radiation with Oncolytic Parvovirus H-1 Infection

Purpose. To elucidate the influence of ionizing radiation (IR) on the oncolytic activity of Parvovirus H-1 (H-1PV) in human high-grade glioma cells. Methods. Short term cultures of human high-grade gliomas were irradiated at different doses and infected with H-1PV. Cell viability was assessed by determining relative numbers of surviving cells. Replication of H-1PV was measured by RT-PCR of viral RNA, fluorescence-activated cell sorter (FACS) analysis and the synthesis of infectious virus particles. To identify a possible mechanism for radiation induced change in the oncolytic activity of H-1PV we performed cell cycle analyses. Results. Previous irradiation rendered glioma cells fully permissive to H-1PV infection. Irradiation 24 hours prior to H-1PV infection led to increased cell killing most notably in radioresistant glioma cells. Intracellular levels of NS-1, the main effector of H-1PV induced cytotoxicity, were elevated after irradiation. S-phase levels were increased one day after irradiation improving S-phase dependent viral replication and cytotoxicity. Conclusion. This study demonstrates intact susceptibility of previously irradiated glioma-cells for H-1PV induced oncolysis. The combination of ionizing radiation followed by H-1PV infection increased viral cytotoxicity, especially in radioresistant gliomas. These findings support the ongoing development of a clinical trial of H-1PV in patients with recurrent glioblastomas

Antioxidant-Induced Changes of the AP-1 Transcription Complex Are Paralleled by a Selective Suppression of Human Papillomavirus Transcription

Although E6 and E7 themselves possess intrinsic trans-activation capacity on their homologous promoters (14, 52), constitutive expression of E6 or E7 in immortalized or malignantly transformed human keratinocytes is mainly dependent on the availability of a defined set of transcription factors derived from the infected host cell. AP-1, for example, normally consisting of a heterodimer between c-Fos and c-Jun (for a review, see reference 4), seems to play a central role in transcriptional regulation of viral oncogene expression, since point mutations of the corresponding consensus sequences within the upstream regulatory region (URR) of HPV-16 or HPV-18 almost completely abolish the expression of URR-driven reporter plasmids in transient transfection assays Recent studies have shown that trans-activation and the DNA-binding affinity of AP-1 (1, 44) as well as that of other transcription factors such as NF-B (65, 78) or p53 (29) can be modulated not only via posttranslational modifications such as phosphorylation or dephosphorylation (for a review, see ref- erence 31) but also by alterations of the intracellular redox status. This can be achieved by certain cytokines, which are able to induce a prooxidant state within the cell by generating reactive oxygen intermediates (ROIs) Similar prooxidant conditions can also be generated either by exposing cells directly to hydrogen peroxide (40) or by genotoxic stress after UV irradiation (60), leading in both cases to the activation of AP-1 (74) and NF-B (44). While such intracellular redox changes are normally counterbalanced by antioxidant enzymes like Cu-Zn-superoxide dismutases (48) or oxidoreductases such as thioredoxin In a previous study, we showed that tumor necrosis factor alpha-induced transcription of a chemokine gene encoding monocyte chemoattractant protein 1 (MCP-1) could be completely abrogated when nonmalignant HPV-positive cells were incubated with PDTC prior to cytokine addition (57). Consistent with the aforementioned model of redox modulation of specific genes, detailed promoter analysis has revealed that NF-B and AP-1 are indeed the predominant transcription factors involved in the regulation of this particular chemokine Since AP-1 is also a central transcription factor for efficien

A non-controlled, single arm, open label, phase II study of intravenous and intratumoral administration of ParvOryx in patients with metastatic, inoperable pancreatic cancer: ParvOryx02 protocol

Background: Metastatic pancreatic cancer has a dismal prognosis, with a mean six-month progression-free survival of approximately 50% and a median survival of about 11 months. Despite intensive research, only slight improvements of clinical outcome could be achieved over the last decades. Hence, new and innovative therapeutic strategies are urgently required. ParvOryx is a drug product containing native parvovirus H-1 (H-1PV). Since H-1PV was shown to exert pronounced anti-neoplastic effects in pre-clinical models of pancreatic cancer, the drug appears to be a promising candidate for treatment of this malignancy. Methods: ParvOryx02 is a non-controlled, single arm, open label, dose-escalating, single center trial. In total seven patients with pancreatic cancer showing at least one hepatic metastasis are to be treated with escalating doses of ParvOryx according to the following schedule: i) 40% of the total dose infused intravenously in equal fractions on four consecutive days, ii) 60% of the total dose injected on a single occasion directly into the hepatic metastasis at varying intervals after intravenous infusions. The main eligibility criteria are: age ≥ 18 years, disease progression despite first-line chemotherapy, and at least one hepatic metastasis. Since it is the second trial within the drug development program, the study primarily explores safety and tolerability after further dose escalation of ParvOryx. The secondary objectives are related to the evaluation of certain aspects of anti-tumor activity and clinical efficacy of the drug. Discussion: This trial strongly contributes to the clinical development program of ParvOryx. The individual hazards for patients included in the current study and the environmental risks are addressed and counteracted adequately. Besides information on safety and tolerability of the treatment after further dose escalation, thorough evaluations of pharmacokinetics and intratumoral spread as well as proof-of-concept (PoC) in pancreatic cancer will be gained in the course of the trial. Trial registration: ClinicalTrials.gov-ID: NCT02653313, Registration date: Dec. 4th, 2015

Oxidative Cleavage of Alkene C=C Bonds Using a Manganese Catalyzed Oxidation with H2O2 Combined with Periodate Oxidation

A one-pot multi-step method for the oxidative cleavage of alkenes to aldehydes/ketones under ambient conditions is described as an alternative to ozonolysis. The first step is a highly efficient manganese catalyzed epoxidation/cis-dihydroxylation of alkenes. This step is followed by an Fe(III) assisted ring opening of the epoxide (where necessary) to a 1,2-diol. Carbon-carbon bond cleavage is achieved by treatment of the diol with sodium periodate. The conditions used in each step are not only compatible with the subsequent step(s), but also provide for increased conversion compared to the equivalent reactions carried out on the isolated intermediate compounds. The described procedure allows for carbon-carbon bond cleavage in the presence of other alkenes, oxidation sensitive moieties and other functional groups; the mild conditions (r.t.) used in all three steps make this a viable general alternative to ozonolysis and especially for use under flow or continuous batch conditions

Describing the chemical bonding in C70 and C70O3 - a quantum chemical topology study

C-c-C-c and C-a-C-b bonds in C-70 have dominant characteristics of double bonds, whereas the remaining six other types of bonds are single bonds with contributions from pi-electron density. `Single' bonds can act as active sites in chemical reactions which would typically require a multiple bond, such as addition of an ozone molecule, due to the fact that all adjacent bonds can serve as an efficient source of pi-electron density. Thus any alteration in the electron density distribution following functionalization has far-reaching impact. We note that formation of the most stable ozonide isomer causes the smallest total perturbation in the electron density of the parent fullerene and C-C bond evolution correlates well with the shape of the minimum energy path for the ozone ring opening reaction on the fullerene surface. Finally, we observe that the O-O bond in C70O3 is protocovalent, and as such resembles the O-O bond in H2O2. (C) 2014 Elsevier B.V. All rights reserved