Förderzeitraum 2015
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- D-1221-2009 (1)
Blood tests are necessary, easy-to-perform and low-cost alternatives for monitoring of oncolytic virotherapy and other biological therapies in translational research. Here we assessed three candidate proteins with the potential to be used as biomarkers in biological fluids: two glucuronidases from E. coli (GusA) and Staphylococcus sp. RLH1 (GusPlus), and the luciferase from Gaussia princeps (GLuc). The three genes encoding these proteins were inserted individually into vaccinia virus GLV-1h68 genome under the control of an identical promoter. The three resulting recombinant viruses were used to infect tumor cells in cultures and human tumor xenografts in nude mice. In contrast to the actively secreted GLuc, the cytoplasmic glucuronidases GusA and GusPlus were released into the supernatants only as a result of virus-mediated oncolysis. GusPlus resulted in the most sensitive detection of enzyme activity under controlled assay conditions in samples containing as little as 1 pg/ml of GusPlus, followed by GusA (25 pg/ml) and GLuc (≥375 pg/ml). Unexpectedly, even though GusA had a lower specific activity compared to GusPlus, the substrate conversion in the serum of tumor-bearing mice injected with the GusA-encoding virus strains was substantially higher than that of GusPlus. This was attributed to a 3.2 fold and 16.2 fold longer half-life of GusA in the blood stream compared to GusPlus and GLuc respectively, thus a more sensitive monitor of virus replication than the other two enzymes. Due to the good correlation between enzymatic activity of expressed marker gene and virus titer, we conclude that the amount of the biomarker protein in the body fluid semiquantitatively represents the amount of virus in the infected tumors which was confirmed by low light imaging. We found GusA to be the most reliable biomarker for monitoring oncolytic virotherapy among the three tested markers.
The LIM and SH3 protein 1 (LASP1) is a focal adhesion protein. Its expression is increased in many malignant tumors. However, little is known about the physiological role of the protein. In the present study, we investigated the expression and function of LASP1 in normal skin, melanocytic nevi and malignant melanoma. In normal skin, a distinct LASP1 expression is visible only in the basal epidermal layer while in nevi LASP1 protein is detected in all melanocytes. Melanoma exhibit no increase in LASP1 mRNA compared to normal skin. In melanocytes, the protein is bound to dynamin and mainly localized at late melanosomes along the edges and at the tips of the cell. Knockdown of LASP1 results in increased melanin concentration in the cells. Collectively, we identified LASP1 as a hitherto unknown protein in melanocytes and as novel partner of dynamin in the physiological process of membrane constriction and melanosome vesicle release.
Background
Anemia is common and is associated with impaired clinical outcomes in diabetic chronic kidney disease (CKD). It may be explained by reduced erythropoietin (EPO) synthesis, but recent data suggest that EPO-resistance and diminished iron availability due to inflammation contribute significantly. In this cohort study, we evaluated the impact of hepcidin-25—the key hormone of iron-metabolism—on clinical outcomes in diabetic patients with CKD along with endogenous EPO levels.
Methods
249 diabetic patients with CKD of any stage, excluding end-stage renal disease (ESRD), were enrolled (2003–2005), if they were not on EPO-stimulating agent and iron therapy. Hepcidin-25 levels were measured by radioimmunoassay. The association of hepcidin-25 at baseline with clinical variables was investigated using linear regression models. All-cause mortality and a composite endpoint of CKD progression (ESRD or doubling of serum creatinine) were analyzed by Cox proportional hazards models.
Results
Patients (age 67 yrs, 53% male, GFR 51 ml/min, hemoglobin 131 g/L, EPO 13.5 U/L, hepcidin-25 62.0 ng/ml) were followed for a median time of 4.2 yrs. Forty-nine patients died (19.7%) and forty (16.1%) patients reached the composite endpoint. Elevated hepcidin levels were independently associated with higher ferritin-levels, lower EPO-levels and impaired kidney function (all p<0.05). Hepcidin was related to mortality, along with its interaction with EPO, older age, greater proteinuria and elevated CRP (all p<0.05). Hepcidin was also predictive for progression of CKD, aside from baseline GFR, proteinuria, low albumin- and hemoglobin-levels and a history of CVD (all p<0.05).
Conclusions
We found hepcidin-25 to be associated with EPO and impaired kidney function in diabetic CKD. Elevated hepcidin-25 and EPO-levels were independent predictors of mortality, while hepcidin-25 was also predictive for progression of CKD. Both hepcidin-25 and EPO may represent important prognostic factors of clinical outcome and have the potential to further define “high risk” populations in CKD.
Background
Schistosomiasis is the most widespread water-based disease in sub-Saharan Africa. Transmission is governed by the spatial distribution of specific freshwater snails that act as intermediate hosts and human water contact patterns. Remote sensing data have been utilized for spatially explicit risk profiling of schistosomiasis. We investigated the potential of remote sensing to characterize habitat conditions of parasite and intermediate host snails and discuss the relevance for public health.
Methodology
We employed high-resolution remote sensing data, environmental field measurements, and ecological data to model environmental suitability for schistosomiasis-related parasite and snail species. The model was developed for Burkina Faso using a habitat suitability index (HSI). The plausibility of remote sensing habitat variables was validated using field measurements. The established model was transferred to different ecological settings in Côte d’Ivoire and validated against readily available survey data from school-aged children.
Principal Findings
Environmental suitability for schistosomiasis transmission was spatially delineated and quantified by seven habitat variables derived from remote sensing data. The strengths and weaknesses highlighted by the plausibility analysis showed that temporal dynamic water and vegetation measures were particularly useful to model parasite and snail habitat suitability, whereas the measurement of water surface temperature and topographic variables did not perform appropriately. The transferability of the model showed significant relations between the HSI and infection prevalence in study sites of Côte d’Ivoire.
Conclusions/Significance
A predictive map of environmental suitability for schistosomiasis transmission can support measures to gain and sustain control. This is particularly relevant as emphasis is shifting from morbidity control to interrupting transmission. Further validation of our mechanistic model needs to be complemented by field data of parasite- and snail-related fitness. Our model provides a useful tool to monitor the development of new hotspots of potential schistosomiasis transmission based on regularly updated remote sensing data.
Schistosomiasis is a widespread water-based disease that puts close to 800 million people at risk of infection with more than 250 million infected, mainly in sub-Saharan Africa. Transmission is governed by the spatial distribution of specific freshwater snails that act as intermediate hosts and the frequency, duration and extent of human bodies exposed to infested water sources during human water contact. Remote sensing data have been utilized for spatially explicit risk profiling of schistosomiasis. Since schistosomiasis risk profiling based on remote sensing data inherits a conceptual drawback if school-based disease prevalence data are directly related to the remote sensing measurements extracted at the location of the school, because the disease transmission usually does not exactly occur at the school, we took the local environment around the schools into account by explicitly linking ecologically relevant environmental information of potential disease transmission sites to survey measurements of disease prevalence. Our models were validated at two sites with different landscapes in Côte d’Ivoire using high- and moderateresolution remote sensing data based on random forest and partial least squares regression. We found that the ecologically relevant modelling approach explained up to 70% of the variation in Schistosoma infection prevalence and performed better compared to a purely pixelbased modelling approach. Furthermore, our study showed that model performance increased as a function of enlarging the school catchment area, confirming the hypothesis that suitable environments for schistosomiasis transmission rarely occur at the location of survey measurements.
Background
The actin cytoskeleton is a hallmark of eukaryotic cells. Its regulation as well as its interaction with other proteins is carefully orchestrated by actin interaction domains. One of the key players is the WH2 motif, which enables binding to actin monomers and filaments and is involved in the regulation of actin nucleation. Contrasting conserved domains, the identification of this motif in protein sequences is challenging, as it is short and poorly conserved.
Findings
To identify divergent members, we combined Hidden-Markov-Model (HMM) to HMM alignments with orthology predictions. Thereby, we identified nearly 500 proteins containing so far not annotated WH2 motifs. This included shootin-1, an actin binding protein involved in neuron polarization. Among others, WH2 motifs of ‘proximal to raf’ (ptr)-orthologs, which are described in the literature, but not annotated in genome databases, were identified.
Conclusion
In summary, we increased the number of WH2 motif containing proteins substantially. This identification of candidate regions for actin interaction could steer their experimental characterization. Furthermore, the approach outlined here can easily be adapted to the identification of divergent members of further domain families.
Background. Intraoperative myelography has been reported for decompression control in multilevel lumbar disease. Cervical myelography is technically more challenging. Modern 3D fluoroscopy may provide a new opportunity supplying multiplanar images. This study was performed to determine the feasibility and image quality of intraoperative cervical myelography using a 3D fluoroscope. Methods. The series included 9 patients with multilevel cervical stenosis. After decompression, 10 mL of water-soluble contrast agent was administered via a lumbar drainage and the operating table was tilted. Thereafter, a 3D fluoroscopy scan (O-Arm) was performed and visually evaluated. Findings. The quality of multiplanar images was sufficient to supply information about the presence of residual stenosis. After instrumentation, metal artifacts lowered image quality. In 3 cases, decompression was continued because myelography depicted residual stenosis. In one case, anterior corpectomy was not completed because myelography showed sufficient decompression after 2-level discectomy. Interpretation. Intraoperative myelography using 3D rotational fluoroscopy is useful for the control of surgical decompression in multilevel spinal stenosis providing images comparable to postmyelographic CT. The long duration of contrast delivery into the cervical spine may be solved by preoperative contrast administration. The method is susceptible to metal artifacts and, therefore, should be applied before metal implants are placed.
We report on a nine-month-old girl who presented with persisting cough, and diminished ventilation of the left hemithorax. Viral pneumonia was suspected after Adenovirus detection by PCR, but chest X-rays showed a persistent shadowing of the left hemithorax and persistent coughing despite clinical improvement. Because of the discrepancy between clinical and radiological signs further investigations by ultrasound and CT scan were performed, which visualized an intrathroracic tumor. Histopathology confirmed diagnosis of a teratoma.
This case highlights the need for careful evaluation by the treating physicians. If the chest X-ray provides a discrepancy to the clinical findings or persistent pathologies exist, differential diagnosis should be discussed and further diagnostics be performed.
It has been demonstrated that verbal context information alters the neural processing of ambiguous faces such as faces with no apparent facial expression. In social anxiety, neutral faces may be implicitly threatening for socially anxious individuals due to their ambiguous nature, but even more so if these neutral faces are put in self-referential negative contexts. Therefore, we measured event-related brain potentials (ERPs) in response to neutral faces which were preceded by affective verbal information (negative, neutral, positive). Participants with low social anxiety (LSA; n = 23) and high social anxiety (HSA; n = 21) were asked to watch and rate valence and arousal of the respective faces while continuous EEG was recorded. ERP analysis revealed that HSA showed elevated P100 amplitudes in response to faces, but reduced structural encoding of faces as indexed by reduced N170 amplitudes. In general, affective context led to an enhanced early posterior negativity (EPN) for negative compared to neutral facial expressions. Moreover, HSA compared to LSA showed enhanced late positive potentials (LPP) to negatively contextualized faces, whereas in LSA this effect was found for faces in positive contexts. Also, HSA rated faces in negative contexts as more negative compared to LSA. These results point at enhanced vigilance for neutral faces regardless of context in HSA, while structural encoding seems to be diminished (avoidance). Interestingly, later components of sustained processing (LPP) indicate that LSA show enhanced visuocortical processing for faces in positive contexts (happy bias), whereas this seems to be the case for negatively contextualized faces in HSA (threat bias). Finally, our results add further new evidence that top-down information in interaction with individual anxiety levels can influence early-stage aspects of visual perception.
The possibility of investigating macroscopic coherent quantum states in polariton condensates and of engineering polariton landscapes in semiconductors has triggered interest in using polaritonic systems to simulate complex many-body phenomena. However, advanced experiments require superior trapping techniques that allow for the engineering of periodic and arbitrary potentials with strong on-site localization, clean condensate formation, and nearest-neighbor coupling. Here we establish a technology that meets these demands and enables strong, potentially tunable trapping without affecting the favorable polariton characteristics. The traps are based on a locally elongated microcavity which can be formed by standard lithography. We observe polariton condensation with non-resonant pumping in single traps and photonic crystal square lattice arrays. In the latter structures, we observe pronounced energy bands, complete band gaps, and spontaneous condensation at the M-point of the Brillouin zone.