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Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancy and projected to be the third leading cause of cancer related death by 2030. Despite extensive knowledge and insights into biological properties and genetic aberrations of pancreatic ductal adenocarcinoma cells, therapeutic options remain temporary and ineffective. One plausible explanation for the futile response to therapy is an insufficient and nonspecific delivery of anticancer drugs to the tumor site. Superparamagnetic iron oxide nanoparticles (SPION) coupled with siRNA targeted against the cell cycle specific serine-threonine-kinase, Polo-like kinase-1 (siPLK1-StAv-SPIONs) could serve a dual purpose for delivery of siPLK1 to tumor and noninvasive assessment of delivery in vivo. siPLK1-StAv-SPIONs were designed as theranostics to function via a membrane translocation peptide (MPAP-) as well as a tumor selective peptide (EPPT-1) to increase intracellular delivery and tumor specificity, respectively. In vitro and in vivo experiments using a syngenic orthotopic PDAC model as well as the endogenous LSL-KrasG12D,LSL-Trp53R172H,Pdx-1-Cre model revealed significant accumulation of siPLK1-StAv-SPIONs in PDAC resulting in efficient PLK1 silencing. Tumor specific silencing of PLK1 halts tumor growth, marked by decrease in tumor cell proliferation and increase in apoptosis. siPLK1-StAv-SPIONs are well tolerated with no observed systemic side effects. Our data suggests, siPLK1-StAv-SPIONs with dual specificity residues for tumor targeting and membrane translocation, represent an exciting opportunity for targeted therapy in PDAC.
This thesis is devoted to experiments on three-dimensional dust clouds which are confined in low temperature plasmas. Such ensembles of highly electrically charged micrometer-sized particles reveal fascinating physics, such as self-excited density waves and vortices. At the same time, these systems are challenging for experimental approaches due to their three-dimensional character. In this thesis, new optical diagnostics for dusty plasmas have been developed and, in combination with existing techniques, have been used to study these 3D dusty plasmas on different size and time scales.
Background: Microvascular Decompression represents an effective treatment for hemifacial spasm. The use of lateral spread responses (LSRs) monitoring remains a useful intraoperative tool to ensure adequate decompression of the facial nerve. Objective: To assess the value of LSRs intraoperative monitoring as a prognostic indicator for the outcome of microvascular decompression in hemifacial spasm. Methods: Our study included 100 patients prospectively. The patients were classified into 4 groups whether LSRs were totally, partially, not relieved or not detected from the start. According to clinical outcome, the patients were classified into 4 groups depending on the clinical course after surgery and the residual symptoms if any. Then, correlations were made between LSRs events and treatment outcome to detect its reliability as a prognostic indicator. Results: LSRs were relieved totally in 56% of the patients, partially relieved in 14%, not relieved in 10% and were not detected in 20% of the patients from the start. HFS was relieved directly after operation in 62% with clinical improvement of 90-100%. 31% described 50-90% improvement over the next 3 months after surgery. Almost all of these 31% (28 out of 31 patients) reported further clinical improvement of 90-100% within one year after surgery. 3% suffered from a relapse after a HFS-free period and 4% reported minimal or no improvement describing 0-50% of the preoperative state. The percentage of the satisfied patients with the clinical outcome who reported after one year a clinical improvement of 90-100% was 90%. Statistical analysis did not find a significant correlation between the relief of LSRs and clinical outcome. Conclusion: LSRs may only represent an intraoperative tool to guide for an adequate decompression but failed to represent a reliable prognostic indicator for treatment outcome.
The role of uptake and efflux transporters in the pharmacokinetics of ß1-receptor blocker talinolol
(2016)
Introduction: The β1-adrenergic receptor antagonist talinolol is a probe drug for P-glycoprotein (P-gp). It is absorbed erratically and incompletely from the gastrointestinal tract. However, its pharmacokinetics might also be influenced by further uptake and efflux transporters as concluded from interaction studies with naringin and verapamil in human. Additionally, the transcellular transport through the different tissues, including enterocytes, hepatocytes and kidney tubular cells, is not completely understood so far. Therefore, we aimed to measure the affinity of talinolol to drug transporting proteins (OCT1-3, PEPT1, OCTN2, ASBT, NTCP, MRP 1-3 and P-gp as well as OATP 1B1, 1B3, 2B1 and 1A2) and some of their genetic variants known to be of pharmacokinetic relevance (OATP1A2 *2 and*3 as well as OATP2B1 V201M, R312Q and S486F). In a further step, we retrospectively evaluated the impact of clinically relevant genetic polymorphisms of transporters on the pharmacokinetics of talinolol in healthy subjects. Materials and Methods: Time and concentration-dependent uptake assays with [3H]-talinolol were performed either in stable transfected HEK293 or MDCKII cells expressing OATP1A2 *1, *2 and *3, OATP1B1, OATP1B3, OATP2B1 (and its genetic variants p.V201M, p.R312Q and p.S486F), NTCP, ASBT, PEPT1, OCTN2, OCT 1-3 and the respective vector control or in inside-out lipovesicles expressing the efflux transporters MRP1-3 and P-gp. Talinolol was quantified by liquid scintillation counting. The transport rates were then corrected by the transporter proteomics measured in the cellular membrane. Regarding the pharmacogenomic evaluation, it was carried out retrospectively in 39 healthy subjects who had participated in former pharmacokinetic studies with talinolol. This evaluation included a variety of transporter related genetic variants, known to be of a clinical meaning for their substrates. Results: Among the uptake transporters, talinolol was shown to be a substrate of OATP1B3 (Km= 153 ± 137 μmol/l; Vmax= 168 ± 30.3 μmol/mgxmin), OATP1B1 (Km= 301 ± 133 μmol/l; Vmax= 1135 ± 348 μmol/mgxmin), OATP2B1 (Km= 459 ± 260 μmol/l; Vmax= 4.32 ± 1.33 μmol/mgxmin), OATP1A2 (Km= 477 ± 158 μmol/l; Vmax= 0.61 ± 0.1 μmol/mgxmin) and NTCP (Km= 2560 ± 781 μmol/l; Vmax= 15944 ± 3741 μmol/mgxmin) but not a substrate of OCT1-3, OCTN2, PEPT1 or ASBT. When it comes to the efflux transporters, talinolol was transported by both P-gp (Km = 175 ± 206 mol/l; Vmax = 14 ± 10.8 nmol/mgxmin) and MRP3 (Km= 86.8 ± 62.8 μmol/l; Vmax= 133 ± 51.5 μmol/mgxmin) but not by MRP2. The pharmacogenomic analysis supported the in-vitro results, as it showed a significant decrease in talinolol absorption (AUC and Cmax) in subjects with the loss of function variant MRP3 211C>T and in those with a decreased P-gp function due to having less than 5 T-allels in the haplotype P-gp 1236-2677-3435-TTT. No significant changes were found associated with other transporters’ genetic variants. Conclusion: Our in-vitro results suggested the vectorial transport of talinolol through the enterocytes to consist mainly of apical OATP2B1 and P-gp and basolateral MRP3. Additionally in the hepatocytes, apical OATP1B1, OATP1B3 and NTCP seem to be involved as well. This vectorial transport was demonstrated in-vivo for the first time by our pharmacogenomic analysis, where talinolol absorption was significantly influenced by both P-gp and MRP3 genetic variants.
This thesis draws a comprehensive picture about the radiation and diversification of truncatelloidean gastropods across the south pacific. It covers three more specifc studies focussing on the Truncelloideans from Fiji, Vanuatu and New Caledonia, respectively. And a conclusive analysis that combines the results of the three more specific studies and enhances them using species from the Austral Islands, Lord Howe Island, the Indonesian island Sulawesi as well as several species from New Zealand and Australia. Molecular phylogenies were calculated using four nuclear gene fragments (ITS2; 18S rRNA; 28S rRNA and Histone 3) besides the mitochondrial COI and 16S rRNA. Further molecuular data was used to calculate dated phylogenies, perform ancestral range reconstructions and develop a modified molecular barcoding approach.
Psychiatric disorders are highly heritable. But the underlying molecular mechanisms are largely unknown or not understood. For many disorders, candidate genes have been proposed which are biologically driven or based on large GWAS studies. In this work different approaches were shown to investigate the impact of genetic risk factors for major psychiatric disorders in the general population. These genetic risk variants include single nucleotide polymorphisms associated with schizophrenia or major depression and were analyzed using the whole-genome information in polygenic scores or candidate marker analysis in GxE studies. Genetic data from SHIP-0 and SHIP-TREND have been used to calculate a polygenic risk score for schizophrenia. Here, the association between this genetic score and brain alterations is shown in three independent samples (SHIP-2, SHIP-TREND and BIG) which revealed no hint of a common genetic basis for schizophrenia and brain structure. These results are in line with other studies that also failed to find a genetic overlap. The same polygenic scores had been used in a PHEWAS analysis in SHIP-0 where an inverse association to migraine was found. This association could be attributed to the NMDA receptor activation via D-serine at the glutamatergic synapse. To assess the impact of environmental factors on the path from genes to phenotype, gene-environment interactions were applied. A significant interaction could be observed between rs7305115 (TPH2) and rs25531 (5-HTTLPR) and childhood abuse on current depression score in SHIP-LEGEND and SHIP-TREND. In summary, genetic variants associated with major psychiatric disorders can exhibit pleiotropic effects on common phenotypes in the general population.
An interesting subclass of the SLs are Cers, the simplest SLs. Cers are assigned a special role within SLs because of their involvement in many cellular and biophysical processes.In literature Cers are describe to modulate many events in signaling including apoptosis. Besides its role as second messenger and therefore the involvement in many signal cascades, Cers are also known to be essential in physical modifications and structural alternations of membranes. Such regulatory functions on membrane formation are e.g. domain formation with other lipids (i.g. SM and Chol), phase separation with sterols (Chol), vesicular trafficking, fusion, membrane curvature fluidity and thickness and the induction of membrane leakiness. In contrast to phospholipids, Cers can move from one side of the membrane leaflet to the other, due to their strong hydrophobicity. This movement is called flip-flop or as transbilayer movement and is controversially discussed. Consequently, no exact value has been reported about the flip-flop property of Cers, which probably plays an important role during the transmission of an extra cellular signal through the membrane.In order to probe the biophysical properties of ceramides, a synthetic access to 1-thioceramides (1-SHCer) analogues with different N-acyl chain length has been developed in this study. With 1SHCer the flip-flop was investigated on pre-formed liposomes and the data indicated a very rapid flip-flop of Cers with a half time t1/2 <10s in raft- and non-raft like membrane models. Furthermore, the acyl chain length exhibited no measurable impact on the speed of the flip-flop. Utilizing the same probes the importance of hydrogen bond donor and acceptor properties of Cers upon interaction with sphingomyelin in the presence or absence of cholesterol (Chol) has been probed. Performed fluorescent quenching experiments (P.Slotte) proposed the following relative preference in interaction with pSM:pSM:DAGs > pSM:Cer > pSM:Chol > pSM: 1-pCerSH.Most strikingly, the importance of the 1-OH H-bond acceptor functionality to replace Chol around and above the melting temperature of pSM has been demonstrated. Recently, an unusual subclass of SLs, named 1-deoxysphingoids have come to the foreground, as biomarker for metabolic disorders. 1-doxSA is physiologically generated (10-40nM) due to substrate promiscuity of SPT and shown to be elevated in patients with metabolic disorders. In this study an organic synthetic access to fluorescent DSB derivatives was established, featuring a fluorescent moiety at the lipid tail, such as FITC 26. Comprehensive fluorescent studies of 26 revealed an unusual subcellular distribution. Exogenous 1-doxSA analogues, such as FB1 and 1-doxSA-FITC, enter via specific entry points. During the next few hours these lipids accumulate within the cytosol prior to N-acylation by CerS. Upon N-acylation, the newly formed 1-doxdhCer and its analogues insert into the ER membrane.The fluorescent probe and most likely FB1 analogues accumulate within the late endosomal and lysosomal system, probably via a direct connection with the ER. Analysis of the lipid metabolism of unlabeled 1-doxSA and FB1 revealed a strikingly similar behavior, pointing towards a common pharmacological effect. Complete consumption of TG within 24h in epithelia cells combined with GO analysis of 1-doxSA interacting lipids indicates significant modulation of fatty acid degradation, pointing towards regulation of the energy metabolism. This is in good agreement with the observed induction of autophagy. Together, this rapid and similar metabolic change of both 1-doxSA and FB1, points toward direct 1-doxSA head-group related lipid-protein interaction and less toward the influence of FB1 on CerS activity. This work suggests the biological significance of 1-doxSA as a primary nutrient sensor to maintain nutrient homeostasis and its role in the pathophysiology of metabolic diseases.
The presented study was dedicated to outstanding issues in regard to the safety and efficacy of the LAV “CP7_E2alf”, during the final licensing process and towards its putative implementation in outbreak scenarios as emergency vaccine. (I) For application of a genetically engineered virus under field conditions, knowledge about its genetic stability is mandatory. Therefore, the genetic stability of “CP7_E2alf” needed to be assessed in vivo and in vitro. Mutation rates were compared to the parental pestivirus strains (BVDV-1 “CP7” and CSFV “Alfort/187”), and BVDV or CSFV field-strains. There was no indication that “CP7_E2alf” could be more prone to mutational events than its parental viruses or representative field-strains. Moreover, no recombination events were observed in in vitro experiments. In conclusion, the data obtained in this study confirm a strong genetic stability of “CP7_E2alf” as an important safety component. (II) Since vaccination of breeding animals is often discussed, this study was conducted to assess the safety of “CP7_E2alf” vaccination of breeding male pigs. The study with “CP7_E2alf” vaccinated boar demonstrated that the new CSFV marker vaccine is suitable for application in reproductive boar. Neither in organs of the uro-genital tract related to sperm production nor in urine or feces, vaccine virus genome was detectable. Dissemination of “CP7_E2alf” through semen, and shedding with urine and feces, is therefore highly unlikely. (III) In order to investigate the influence of pre-existing pestivirus antibodies of the efficacy of “CP7_E2alf”, a vaccination-challenge-trial was conducted with “CP7_E2alf” (Suvaxyn® CSF Marker) and the “gold-standard” of live-modified CSFV vaccines, the C-strain (RIEMSER® Schweinepestvakzine). Pre-existing antibodies against BVDV-1 were provoked through intramuscular inoculation of a recent field isolate from Germany. Seven days after the vaccination, all animals were challenged with highly virulent CSFV strain “Koslov”. It was demonstrated that pre-existing anti- BVDV-1 antibodies do not impact the efficacy of both live attenuated vaccines against CSFV. Both C-strain “Riems” and marker vaccine “CP7_E2alf” were able to confer full protection against the highly virulent challenge. However, slight interference was seen with serological DIVA diagnostics accompanying “CP7_E2alf”. Amended sample preparation and combination of test systems was able to resolve most cases of false positive reactions. However, in such a coinfection scenario, optimization and embedding in a well-defined surveillance strategy is clearly needed for marker vaccination scenarios. (IV) To supplement the data about the kinetic of maternally derived antibodies in piglets from sows vaccinated during outbreaks, a single “emergency-type” vaccination of two pregnant sows was done. Focus was laid on the kinetics of maternally derived antibodies (MDA) in the screening assays of their offspring with screening assays that would be used in case of CSFV outbreaks, i.e. CSFV E2 and Erns antibody ELISA. Upon vaccination with “CP7_E2alf” 21 days before farrowing, MDAs were measurable in all piglets born to vaccinated sows. The E2- ELISA reactivities showed an almost linear decrease over ten weeks after which all piglets were tested negative in the ELISA. Future studies should investigate, if MDA are able to protect offspring of vaccinated sows or whether the piglets should also be vaccinated.
Hantaviruses are enveloped viruses with a single-stranded RNA genome of negative polarity. The genome consists of three segments: small (S), medium (M) and large (L). As zoonotic pathogen, hantaviruses are worldwide responsible for 150,000 to 200,000 human disease cases per year. Two forms of human disease are currently distinguished: In the Americas the hantavirus cardiopulmonary syndrome (HCPS) and in Europe and Asia the hemorrhagic fever with renal syndrome (HFRS). Since the introduction of the German Protection against Infection Act in 2001 until now a total of 10,082 disease cases have been reported. As a result, hantavirus infections currently rank as the fifth frequent notifiable disease in Germany. More than 80% of these infections were caused by the hantavirus species Puumala virus (PUUV), transmitted by the bank vole Myodes glareolus. Besides temporal oscillations, an unequal geographical distribution of human PUUV cases was noticed in Germany and in other countries of Central Europe. This is reflected in the presence of endemic and non-endemic regions as well as of so-called outbreak years. Therefore, the overall objective of this study was to find out possible reasons for the inhomogeneous distribution of PUUV in Central Europe, in particular in Poland, Germany and certain districts of Baden-Wuerttemberg. The basic working hypothesis was that PUUV spread in Central Europe after the last glaciation with different evolutionary lineages of the bank vole and that the current emergence of PUUV in bank vole populations is determined by local geographical and ecological factors. Very little was known about the presence of PUUV in Poland. Earlier studies were based exclusively on serological detection of PUUV, but a molecular detection with subsequent phylogenetic investigation was missing so far. Therefore, 45 bank voles from the northeastern part of Poland were investigated by serological and molecular assays. In three animals from a forest region close to the city of Miko³ajki PUUV-reactive antibodies and/or PUUV RNA were detected. Phylogenetic analysis indicated the presence of a Latvian (LAT) PUUV strain. Viral RNA was detected in one bank vole of the Eastern evolutionary lineage and two animals of the Carpathian lineage. Thereby it could be demonstrated for the first time that the distribution of the LAT PUUV lineage ranges from Latvia south-west to the northeastern part of Poland. An inhomogeneous spatial distribution of human disease cases has been observed even for Baden-Wuerttemberg, a long time known endemic federal state of Germany. Therefore 660 bank voles were trapped during the outbreak and non-outbreak years 2012 and 2013 in four districts with high incidences (H) and in four districts with low incidences or lacking PUUV cases (L). During the outbreak year 2012 PUUV-positive bank voles were detected by serological and molecular investigations in seven of eight districts. In contrast, in the following year only in one district PUUV infected bank voles were detected. Furthermore, it was demonstrated that after a beech mast, i.e., a massive fructification of beech trees, in H districts with a higher percentage of beech forest coverage a higher number of human cases was notified, but not in L districts with a lower percentage of beech forest coverage. For the future development of early warning modules it is therefore necessary to have a long-term bank vole monitoring established that incorporates beech mast data and information on beech forest coverage. High endemic regions for PUUV are mainly located in the southern and western parts of Germany, whereas in the eastern and northern parts only low numbers or even no human cases are recorded. To find out possible reasons for this inhomogeneous distribution, 1,774 bank voles from different regions of Germany were investigated for PUUV infections and in parallel for the corresponding bank vole evolutionary lineage (Western, Eastern, Carpathian). The PUUV investigations indicated positive voles in the known endemic regions with an easternmost and northernmost occurrence in western Saxony-Anhalt, western Thuringia and in Osnabrück. In the northern and eastern part of Germany none of the 1,210 investigated bank voles showed a PUUV infection. In the southern and western parts of Germany only the Western bank vole lineage was identified, whereas the Eastern lineage was exclusively found in the eastern and northern part and the Carpathian lineage in the South-East and North-East of Germany. PUUV infections were found almost exclusively in bank voles of the Western lineage. Individuals of the other two vole lineages were found to be PUUV infected only in regions with sympatric occurrence of the Western lineage. The previously described contact zone of the different bank vole phylogroups ranges from Poland to the entire northern part of Germany. In conclusion, the results of this investigation indicate two potential major reasons for the inhomogeneous distribution of PUUV in Germany: First, PUUV of the CE lineage seems to be associated with the Western bank vole lineage. The current geographical distribution of virus and host might be explained by a post-glacial northern expansion of the bank vole starting at the western refuge. Second, the missing detection of PUUV in bank voles of the Western lineage in areas close to high endemic regions might be explained by the extinction of the virus due to a limited winter survival of infected animals during long and harsh winters. The virus stability outside the host or ecological barriers, such as isolated forest areas or broad rivers, might also influence the distribution of PUUV in bank vole populations.
In this thesis, rates and extend as well as the ecological implications of electron exchange reactions that involve redox-active moieties in organic matter (OM) were explored. The research builds on earlier findings that confirmed that OM may act as terminal electron acceptor (TEA) for electrons released in microbial respiration. This property was associated with quinone moieties that are ubiquitously found in OM from terrestrial and aquatic environments and that may undergo reversible reduction to the respective hydroquinone. Earlier methodological advances allowed for a rapid, direct and precise quantification of the electron accepting and donating properties of quinones in dissolved OM (DOM) by mediated electrochemical analysis. In this work, the previously established mediated electrochemical analysis was adapted and used in the characterization of redox properties of particulate natural samples that contain redox active iron and organic matter ("geochemical phases"). For the first time, direct measurements confirmed that microorganisms transferred electrons (e) from microbial respiration to the organic and inorganic electron acceptors in the particulate phase. Particulate OM in the sediments was found to provide a capacity to accept or donate e of 650 µmol e/gC. An incubation experiment resolved the spatiotemporal dynamics of organic and inorganic TEA species (i.e., nitrate, sulfate, Fe- and Mn oxyhydroxides) in sediments upon changes in oxygen availability and hence redox conditions. Oxygen is consumed when the reduced species are oxidized and, by this means, re-generate their electron-accepting capacity. The use of mediated electrochemical analysis allowed for the quantification of the redox state of the geochemical phases during their reduction and re-oxidation. The electron fluxes initiated by the oxic re generation of the TEAs nitrate, sulfate, Fe(III), Mn(IV) and quinoid moieties in OM were therefore directly monitored instead of modeled from the species’ distribution profiles in interstitial waters. The cyclic reduction and re-oxidation of redox species exposed to oxygen fluctuations was suspected to be a critical component of many aquatic ecosystems. In stratified lakes, extended sediment volumes are exposed to oxygen only upon lake overturn. Lake oxygen budgets are therefore influenced by benthic redox processes. The combined field and laboratory study showed that lake overturn seasonally introduces a finite amount of oxygen to the hypolimnion and that about 50% of the subsequent sediment oxygen consumption is exclusively associated with the re-generation of TEA species. These species previously formed in the sediment when organic matter was microbially decomposed during anaerobia. While lake overturn can completely mix epi- and hypolimnetic waters, small-scaled dynamics in temperature and oxygen availability may confine discrete parts of the water column with oscillations in physicochemical conditions. In the studied lake, a transient thermocline cyclically introduces oxygen to hypoxic hyplimnetic waters close to the pelagic redox interface. In the lake, organic TEAs may represent an important component of the total pelagic electron acceptor capacity. Due to the rapid and reversible redox reactions of DOM, reduced organic TEAs are re-generated upon dislocation to oxic parts of the water column. Results show that diurnal fluctuations of oxycline depth shape a micro-environment selecting for microbial species that are released from TEA limitations by OM in oxidized state. Pelagic microbial communities subjected to the same amount of OM in different oxidation states differed by more than 50% after one day. This work substantiates earlier findings that suggested that OM may be an important TEA species in many aquatic and terrestrial ecosystems. OM reduction in microbial respiration was shown to directly affect critical system parameters as bacterial activity, oxygen budgets and aquatic biodiversity. Both the microbial reduction and subsequent abiotic oxidation of OM are sufficiently fast for relevant interaction with oxycline fluctuation on different timescales. Given that organic TEAs are cyclically regenerated, a significant share of ecosystem respiration could be linked to OM reduction. This thesis demonstrated the new and important role electron exchange reactions in OM-rich environments play and explored the mechanism of this previously neglected part of lake functioning. As of today, linking the chemistry of aquatic turnover processes with the microbiological and physical conditions at redox interfaces remains challenging. In conclusions, by providing several cases from aquatic environments, this thesis contributes to the mechanistic understanding of OM reduction in microbial respiration. The results prompt for further research regarding the competitive inhibition of other respiration pathways, including the reductive production of the potent greenhouse gas methane.