Clinical trials with anti-angiogenic agents in hematological malignancies

New blood vessel formation (angiogenesis) is not only essential for the growth of solid tumors but there is also emerging evidence that progression of hematological malignancies like multiple myeloma, acute leukemias, and myeloproliferative neoplasms, also depends on new blood vessel formation. Anti-angiogenic strategies have become an important therapeutic modality for solid tumors. Several anti-angiogenic agents targeting angiogenesis-related pathways like monoclonal antibodies, receptor tyrosine kinase inhibitors, immunomodulatory drugs, and proteasome inhibitors have been entered clinical trials or have been already approved for the treatment of hematological malignancies as well and in some instances these pathways have emerged as promising therapeutic targets. This review summarizes recent advances in the basic understanding of the role of angiogenesis in hematological malignancies and clinical trials with novel therapeutic approaches targeting angiogenesis

Development of power supply unit for LED automotive headlamp

Diplomsko delo obravnava razvoj napajalnika za žaromete iz svetlečih diod (ang. LED), od ideje in zasnove, do testiranja vezja in končnega izdelka. Prvo poglavje je namenjeno kratkemu pregledu različnih avtomobilskih žarometov. Opisane so svetleče diode in njihovo delovanje. Na avtomobilu je več svetil za različne aplikacije, zato so pomembne tudi barve LED. Spustili se bomo v delovanje, strukturo in karakteristiko bele LED, saj nam bodo ti podatki pogoj za izdelavo napajalnika. V drugem poglavju spoznamo več različnih načinov napajanja LED. Osredotočimo se na stikalne napajalnike. Razložimo njihovo delovanje in prednosti. Razvoj stikalnega napajalnika navzdol za LED v avtomobilskih žarometih opišemo v naslednjem poglavju. Začnemo z izbiro ustreznega integriranega vezja na podlagi naših zahtev ter izdelavo sheme vezja. Pod bolj kompleksne zahteve sodijo še dodatne zaščite, kot so zaščita proti prekomerni vhodni napetosti ter temperaturna zaščita. Da dosežemo uporabo LED žarometa v dveh aplikacijah, recimo dnevna luč in pozicija z eno LED, uporabimo pulzno širinsko modulacijo za nastavljanje svetilnosti. Po izdelavi shematike se posvetimo detajlni zasnovi in realizaciji tiskanega vezja. Tiskanina mora biti sistematično izrisana, tako da napajalnik pravilno deluje in ustreza elektromagnetni kompatibilnosti brez kakršnih motenj. Za lažjo izdelavo si pomagamo z napotkom za izdelavo tiskanega vezja za izbrano integrirano vezje, ki se nahaja v podatkovnem listu integriranega vezja. Na izdelanem vezju izvedemo električne teste in teste elektromagnetne kompatibilnosti. Ker imajo stikalni pretvorniki zelo dober izkoristek, se v tem delu ne bomo ukvarjali s temperaturnimi težavami ampak s težavami elektromagnetne kompatibilnosti, ki so vedno prisotni.The thesis deals with the development of the power supply for automotive LED headlamps, from idea and concept to the testing of electronic circuit and the final product. The first chapter is devoted to the review of the history of automotive headlamps. Described are the light-emitting diodes (LEDs) and their functions. On the car there are more lights for different applications, so relevant is also color of LED. We will let in the operation, structure and characteristics of white LEDs, because all of these data are required to design a power supply. In the second chapter we will get to know many different ways to drive an LED. We focus on switching power supplies. We explain their operation and advantages. The development of switching power supply for LED headlamp is described in next chapter. We start by selecting the appropriate integrated circuit based on our requirements and start with making schematics. Under the more complex requirements belong additional protections, such as overvoltage and thermal protection. In order to achieve the usage of the headlamp in the two applications, such as daytime runing lamp and the position lamp with the single LED, the pulse-width modulation is used to adjust luminous intensity. After the schematic is created, we devote to detail design and realization of PCB (printed circuit board) layout. The PCB must be systematically drawn so that the LED driver is working properly and meets the electromagnetic compatibility (EMC) without any interference. For easier design, we follow the layout guideline for chosen integrated circuit which can be found in datasheet of integrated circuit. On produced printed circuit board we perform electrical tests and tests of electromagnetic compatibility. Since switching converters have a very good efficiency we won’t deal with temperature problems but problems of electromagnetic compatibility, which are always present

Metronomic antiangiogenic therapy with capecitabine and celecoxib in advanced tumor patients--results of a phase II study

Combined therapy of continuous low dose capecitabine and high dose celecoxib targeting angiogenesis was used in a phase II trial to treat advanced cancer patients. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used to monitor antiangiogenic effects.; 37 Patients (21 men, 16 women), mean age 60 years, with advanced and progressive cancer of various tumor types were included. Therapy consisted of 2 x 500 mg oral capecitabine/ day and 2 x 400 mg oral celecoxib/day continuously until progression of disease. To monitor antiangiogenic effects, DCE-MRI measurements were performed at baseline, after 1 month, and after 3 months of therapy. Tumor assessment was performed according to RECIST criteria, toxicity was evaluated according to the CTC version 2.0 catalogue.; Therapy was well tolerated without grade 3 and 4 toxicities. The mean number of treatment cycles was 4 (range: 1-15+). Disease stabilization after 3 cycles was seen in 11 patients. 6 patients were stable over long periods. The mean number of treatment cycles in this group was 10 (range: 7-15+). DCE-MRI demonstrated a reduction of tumor vessel permeability and blood flow in patients who reached stable disease or some minor regression.; Continuous dosing of the combination of capecitabine and celecoxib was well tolerated, produced antiangiogenic effects, and has antitumor activity. Patients with rapid progression did not benefit

Polo-like kinase 1 (PLK1) inhibition suppresses cell growth and enhances radiation sensitivity in medulloblastoma cells

<p>Abstract</p> <p>Background</p> <p>Medulloblastoma is the most common malignant brain tumor in children and remains a therapeutic challenge due to its significant therapy-related morbidity. Polo-like kinase 1 (<it>PLK1</it>) is highly expressed in many cancers and regulates critical steps in mitotic progression. Recent studies suggest that targeting PLK1 with small molecule inhibitors is a promising approach to tumor therapy.</p> <p>Methods</p> <p>We examined the expression of <it>PLK1 </it>mRNA in medulloblastoma tumor samples using microarray analysis. The impact of PLK1 on cell proliferation was evaluated by depleting expression with RNA interference (RNAi) or by inhibiting function with the small molecule inhibitor BI 2536. Colony formation studies were performed to examine the impact of BI 2536 on medulloblastoma cell radiosensitivity. In addition, the impact of depleting <it>PLK1 </it>mRNA on tumor-initiating cells was evaluated using tumor sphere assays.</p> <p>Results</p> <p>Analysis of gene expression in two independent cohorts revealed that <it>PLK1 </it>mRNA is overexpressed in some, but not all, medulloblastoma patient samples when compared to normal cerebellum. Inhibition of PLK1 by RNAi significantly decreased medulloblastoma cell proliferation and clonogenic potential and increased cell apoptosis. Similarly, a low nanomolar concentration of BI 2536, a small molecule inhibitor of PLK1, potently inhibited cell growth, strongly suppressed the colony-forming ability, and increased cellular apoptosis of medulloblastoma cells. Furthermore, BI 2536 pretreatment sensitized medulloblastoma cells to ionizing radiation. Inhibition of PLK1 impaired tumor sphere formation of medulloblastoma cells and decreased the expression of SRY (sex determining region Y)-box 2 (<it>SOX2</it>) mRNA in tumor spheres indicating a possible role in targeting tumor inititiating cells.</p> <p>Conclusions</p> <p>Our data suggest that targeting PLK1 with small molecule inhibitors, in combination with radiation therapy, is a novel strategy in the treatment of medulloblastoma that warrants further investigation.</p

Study of enzyme sensors with wide, adjustable measurement ranges for in-situ monitoring of biotechnological processes

© 2016 Elsevier B.V. We report on a study of enzymatic glucose and lactate sensors for measurements of wide concentration ranges from 1 mM up to 600 mM and 900 mM, respectively, in biotechnological processes. Diffusion-limiting polyurethane membranes were used to extend the linear measurement range and the influence of two fabrication parameters on membrane properties and sensor performance evaluated. The polymer concentration was varied between 4% and 10% and the ratio of the solvents tetrahydrofuran and dimethylformamide between 9:1 and 1:9. Surface morphology and permeability of the membranes and the linear measurement range of membrane-covered enzyme sensors were determined. A distinct relationship between the different results was found. The sensors retained their functionality after being sterilized using gamma and electron beam irradiation. The long-term performance of the sensors was evaluated and good performance in the glucose monitoring of a culture of Saccharomyces cerevisiae over 13 days was shown.status: publishe

Integrated multi-sensor system for parallel in-situ monitoring of cell nutrients, metabolites, cell density and pH in biotechnological processes

© 2016 Elsevier B.V. We report on a multi-sensor system for the parallel in-situ monitoring of cell nutrients, metabolites, cell density and pH in biotechnological processes. The fabrication process of the sensor chip, based on a CMOS process flow, is suitable for integration into standard processes and mass production of the system. The integration of enzyme sensors for wide concentration ranges, an impedance-based sensor and a pH sensor on one silicon chip for in-situ applications in bioreactors, fabricated in a CMOS-based process flow, is demonstrated for the first time to our best knowledge. Measurements of glucose and lactate concentrations in a wide range are shown with linear ranges up to 600 mM and 900 mM, respectively. Cell density is determined via conductivity changes of a cell suspension and measurements are performed up to 15 g/l dry cell weight. The pH sensor is based on C-V measurements at an electrolyte-insulator-semiconductor structure and able to measure pH in a range from pH 3 to pH 12. All sensors are successfully employed in the monitoring of cultures of Saccharomyces cerevisiae or Lactobacillus acidophilus.status: publishe

Study of enzyme sensors with wide, adjustable measurement ranges for in-situ monitoring of biotechnological processes

peer reviewedWe report on a study of enzymatic glucose and lactate sensors for measurements of wide concentration ranges from 1 mM up to 600 mM and 900 mM, respectively, in biotechnological processes. Diffusion-limiting polyurethane membranes were used to extend the linear measurement range and the influence of two fabrication parameters on membrane properties and sensor performance evaluated. The polymer concentration was varied between 4% and 10% and the ratio of the solvents tetrahydrofuran and dimethylformamide between 9:1 and 1:9. Surface morphology and permeability of the membranes and the linear measurement range of membrane-covered enzyme sensors were determined. A distinct relationship between the different results was found. The sensors retained their functionality after being sterilized using gamma and electron beam irradiation. The long-term performance of the sensors was evaluated and good performance in the glucose monitoring of a culture of Saccharomyces cerevisiae over 13 days was shown. © 2016 Elsevier B.V

Integrated multi-sensor system for parallel in-situ monitoring of cell nutrients, metabolites and cell mass in biotechnological processes

peer reviewe

CMOS potentiostat and sensor with multilayer membrane for wide range measurements of glucos concentrations

peer reviewe