Refine
Document Type
- Article (4)
- Conference Proceeding (1)
- Doctoral Thesis (1)
Language
- English (6)
Has Fulltext
- yes (6)
Is part of the Bibliography
- no (6)
Keywords
- penile cancer (2)
- targeted therapy (2)
- AKT (1)
- Bacterial physiology (1)
- Dünnschichttransistor (1)
- Feldeffekt (1)
- Feldeffekttransistor (1)
- Field-effect (1)
- High-k dielectric (1)
- High-k-Dielektrikum (1)
Institute
- Medizin (4)
- Biowissenschaften (1)
- Physik (1)
This work deals with the use of dielectrics with high permeability, so-called high-k dielectrics in organic thin-film field-effect transistors (FETs). The central part was the preparation of the high-k dielectric and its implementation in transistors, in which organic semiconductors were used as active layer. A field-effect transistor can be used to measure the charge carrier mobility. Employing high-k dielectrics the carrier concentration in the active layer can be greatly increased. In this way, high charge carrier concentrations in organic layers can be achieved without chemical doping. As high-k dielectric strontium titanate (STO) was selected. It is also available as a niobium-doped and therefore conducting substrate material. Thus, one has an ideal substrate for the growth of the dielectric layer in conjunction with a substrate which acts as gate electrode. As the organic semiconductor the small molecules pentacene and copper phthalocyanine (CuPc) were sublimated, as electrical contacts gold was used. As a key part of this work an ultra high vacuum chamber system was constructed for in situ preparation of field effect transistors. For the deposition of the organic thin films a molecular beam deposition chamber was built, including a manipulator and effusion cells as evaporation sources. For the preparation of the dielectric a sputtering chamber was set-up. Another chamber was used in conjunction with an effusion cell for the deposition of the gold contacts. For the structured deposition of the different layers in the devices a shadow mask system was implemented. Movable masks could be positioned by means of a wobble stick onto the sample carriers. The system thus allowed for the use of masks in all chambers. The different thin films required in the transistor structure were first individually prepared and characterized. For the characterization primarily X-ray diffraction and optical microscopy were used. The growth of pentacene was analyzed on aplha-AlO substrates. With X-ray diffraction the (00l) reflections of the thin film phase were observed. In growth studies of CuPc aplha-AlO and STO substrates were used. With X-ray diffraction the aplha-phase was detected. With increasing substrate temperature an increase in crystallinity, but also an increase in surface roughness was observed. The sputtering of STO as a high-k dielectric was studied and optimized. Simultaneously, a high deposition rate, a smooth film surface and good crystallinity of the layer were required. As the most important parameters the substrate temperature, pressure and sputtering power were identified. Argon and oxygen were employed as sputtering gases, as substrate MgO was used. The films showed in comparison to crystalline STO a distortion to larger lattice constants. The degree of distortion decreased with increasing chamber pressure, on the other hand, deposition rate decreased with increasing chamber pressure as well. By combining the individual deposition processes FETs in bottom-gate geometry were prepared. The first step was always sputtering of the STO dielectric on niobium-doped STO substrates. Subsequently, the electrodes and the organic layer were deposited. For comparison transistors on silicon substrates with silicon dioxide (SiO2) as the dielectric were prepared. To study the transistor properties a measurement setup was build. A dielectric constant of about 190 for the STO in the transistors was achieved. The transistors with CuPc as active layer showed p-type conduction behavior. The transistors with STO as dielectric had a much stronger response than those with SiO2. They reached mobilities of 2E-4 cm2/Vs at very low applied voltages of 3V. It could thus be demonstrated that STO is suitable as a dielectric for organic FETs, and that through the use of high-k dielectrics high charge carrier densities can be achieved.
Flavin-based electron bifurcation is a long hidden mechanism of energetic coupling present mainly in anaerobic bacteria and archaea that suffer from energy limitations in their environment. Electron bifurcation saves precious cellular ATP and enables lithotrophic life of acetate-forming (acetogenic) bacteria that grow on H2 + CO2 by the only pathway that combines CO2 fixation with ATP synthesis, the Wood–Ljungdahl pathway. The energy barrier for the endergonic reduction of NADP+, an electron carrier in the Wood–Ljungdahl pathway, with NADH as reductant is overcome by an electron-bifurcating, ferredoxin-dependent transhydrogenase (Nfn) but many acetogens lack nfn genes. We have purified a ferredoxin-dependent NADH:NADP+ oxidoreductase from Sporomusa ovata, characterized the enzyme biochemically and identified the encoding genes. These studies led to the identification of a novel, Sporomusa type Nfn (Stn), built from existing modules of enzymes such as the soluble [Fe–Fe] hydrogenase, that is widespread in acetogens and other anaerobic bacteria.
Introduction: Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin's lymphoma in a real-life clinical setting.
Methods: Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators.
Results: A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician's visual analogue scale; mean improvement from baseline of 12.1 mm).
Conclusions: Data from this registry indicate that rituximab is a commonly employed, well-tolerated therapy with potential beneficial effects in standard of care-refractory autoimmune diseases, and support the results from other open-label, uncontrolled studies.
Simple Summary: Penile cancer is a rare but aggressive malignancy characterized by rapid tumor growth as well as prompt metastasis in groin lymphatics. While localized diseases can be successfully cured by surgery in most cases, no truly effective treatment options have been established for metastatic diseases as of yet. In the current investigation, we assessed the value of selected members of the PI3K/mTOR/AKT pathway to serve as tumor markers or therapeutic targets for this disease. Higher expression of AKT was significantly more prevalent in high-grade tumors and independently predictive of the worse survival parameters, while increased expression of pmTOR was associated with an inferior prognosis as well. Treatment with the pan-AKT inhibitor capivasertib in PeCa cell lines induced significant reduction of cell viability and movement capacity. These findings might aid in the understanding of the molecular tumor background as well as development of novel treatment options for advanced penile cancer.
Abstract: The PI3K/mTOR/AKT pathway might represent an intriguing option for treatment of penile cancer (PeCa). We aimed to assess whether members of this pathway might serve as biomarkers and targets for systemic therapy. Tissue of primary cancer from treatment-naïve PeCa patients was used for tissue microarray analysis. Immunohistochemical staining was performed with antibodies against AKT, pAKT, mTOR, pmTOR, pS6, pPRAS, p4EBP1, S6K1 and pp70S6K. Protein expression was correlated with clinicopathological characteristics as well as overall survival (OS), disease-specific survival (DSS), recurrence-free survival (RFS) and metastasis-free survival (MFS). AKT inhibition was tested in two primarily established, treatment-naïve PeCa cell lines by treatment with capivasertib and analysis of cell viability and chemotaxis. A total of 76 patients surgically treated for invasive PeCa were included. Higher expression of AKT was significantly more prevalent in high-grade tumors and predictive of DSS and OS in the Kaplan–Meier analysis, and an independent predictor of worse OS and DSS in the multivariate regression analysis. Treatment with pan-AKT inhibitor capivasertib in PeCa cell lines induced a significant downregulation of both total AKT and pAKT as well as decreased cell viability and chemotaxis. Selected protein candidates of the mTOR/AKT signaling pathway demonstrate association with histological and survival parameters of PeCa patients, whereas AKT appears to be the most promising one.
Whereas the lack of biomarkers in penile cancer (PeCa) impedes the development of efficacious treatment protocols, preliminary evidence suggests that c-MET and associated signaling elements may be dysregulated in this disorder. In the following study, we investigated whether c-MET and associated key molecular elements may have prognostic and therapeutic utility in PeCa. Formalin-fixed, paraffin-embedded tumor tissue from therapy-naïve patients with invasive PeCa was used for tissue microarray (TMA) analysis. Immunohistochemical staining was performed to determine the expression of the proteins c-MET, PPARg, β-catenin, snail, survivin, and n-MYC. In total, 94 PeCa patients with available tumor tissue were included. The median age was 64.9 years. High-grade tumors were present in 23.4%, and high-risk HPV was detected in 25.5%. The median follow-up was 32.5 months. High expression of snail was associated with HPV-positive tumors. Expression of β-catenin was inversely associated with grading. In both univariate COX regression analysis and the log-rank test, an increased expression of PPARg and c-MET was predictive of inferior disease-specific survival (DSS). Moreover, in multivariate analysis, a higher expression of c-MET was independently associated with worse DSS. Blocking c-MET with cabozantinib and tivantinib induced a significant decrease in viability in the primary PeCa cell line UKF-PeC3 isolated from the tumor tissue as well as in cisplatin- and osimertinib-resistant sublines. Strikingly, a higher sensitivity to tivantinib could be detected in the latter, pointing to the promising option of utilizing this agent in the second-line treatment setting.