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Background: BI 2536, a novel Polo-like kinase 1 inhibitor, was assessed in patients with unresectable advanced exocrine adenocarcinoma of the pancreas. Methods: The study employed a two-stage design. Randomised first-line patients received BI 2536 200 mg on day 1 (n=43) or 60 mg on days 1-3 (n=43) every 21 days. Recruitment of second-line patients was planned for a second stage dependent on an interim analysis demonstrating ≥2 responses in the first 18 evaluable patients following 12 weeks of treatment and/or tumour control ≥12 weeks in 5 patients per schedule. Primary end point was objective response rate (ORR). Results: By independent review, ORR was 2.3% (all partial) and 24.4% had stable disease as confirmed best response. The second stage was not initiated. Median overall and progression-free survivals were 149 (95% confidence interval (CI), 91-307) and 46 days (95% CI, 44-56). Most common drug-related adverse events were neutropenia (37.2%), leukopenia (29.1%), fatigue (29.1%) and nausea (22.1%); most common grade 3/4-related events were neutropenia (36.0%), leukopenia (27.9%) and thrombocytopenia (8.1%). Conclusion: Given the low ORR and poor survival, further development of BI 2536 monotherapy is not warranted in this population. © 2012 Cancer Research UK All rights reserved.

We consider stationary Poisson–Voronoi tessellations (PVT) in the Euclidean plane and study the properties of Voronoi tessellations induced by linear Poisson processes on the edges of the PVT. We are especially interested in simulation algorithms for the typical cell. Two different simulation algorithms are introduced. The first algorithm directly simulates the typical cell, whereas the second algorithm simulates cells from which distributional properties of the typical cell can be obtained. This second algorithm can also be used for simulating the typical cell of other Cox–Voronoi tessellations. The implementation of both algorithms is tested for their correctness using random software tests. Then different cell characteristics are studied by simulation and compared with the typical cell of PVT and Cox–Voronoi tessellations based on linear Poisson processes on the lines of Poisson line processes. Our results can be applied, for example, in the analysis of telecommunication networks and vesicle paths on c...

Keratin intermediate filament networks are part of the cytoskeleton in epithelial cells. They were found to regulate viscoelastic properties and motility of cancer cells. Due to unique biochemical properties of keratin polymers, the knowledge of the mechanisms controlling keratin network formation is incomplete. A combination of deterministic and stochastic modeling techniques can be a valuable source of information since they can describe known mechanisms of network evolution while reflecting the uncertainty with respect to a variety of molecular events. We applied the concept of piecewise-deterministic Markov processes to the modeling of keratin network formation with high spatiotemporal resolution. The deterministic component describes the diffusion-driven evolution of a pool of soluble keratin filament precursors fueling various network formation processes. Instants of network formation events are determined by a stochastic point process on the time axis. A probability distribution controlled by model parameters exercises control over the frequency of different mechanisms of network formation to be triggered. Locations of the network formation events are assigned dependent on the spatial distribution of the soluble pool of filament precursors. Based on this modeling approach, simulation studies revealed that the architecture of keratin networks mostly depends on the balance between filament elongation and branching processes. The spatial distribution of network mesh size, which strongly influences the mechanical characteristics of filament networks, is modulated by lateral annealing processes. This mechanism which is a specific feature of intermediate filament networks appears to be a major and fast regulator of cell mechanics.

We consider modulated Poisson--Voronoi tessellations, intended as models for telecommunication networks on a nationwide scale. By introducing an algorithm for the simulation of the typical cell of the latter tessellation, we lay the mathematical foundation for such a global analysis. A modulated Poisson--Voronoi tessellation has an intensity which is spatially variable and, hence, is able to provide a broad spectrum of model scenarios. Nevertheless, the considered tessellation model is stationary and we consider the case where the modulation is generated by a Boolean germ-grain model with circular grains. These circular grains may either have a deterministic or random but bounded radius. Furthermore, based on the introduced simulation algorithm for the typical cell and on Neveu's exchange formula for Palm probability measures, we show how to estimate the mean distance from a randomly chosen location to its nearest Voronoi cell nucleus. The latter distance is interpreted as an important basic cost characteristic in telecommunication networks, especially for the computation of more sophisticated functionals later on. Said location is chosen at random among the points of another modulated Poisson process where the modulation is generated by the same Boolean model as for the nuclei. The case of a completely random placement for the considered location is thereby included as a special case. The estimation of the cost functional is performed in a way such that a simulation of the location placement is not necessary. Test methods for the correctness of the algorithm based on tests for random software are briefly discussed. Numerical examples are provided for characteristics of the typical cell as well as for the cost functional. We conclude with some remarks about extensions and modifications of the model regarded in this paper, like modulated Poisson--Delaunay tessellations.

SUMMARY Spatial point patterns generated from bitmaps of images of processed reflection seismic profiles are analysed to quantify the reflectivity patterns. The point process characteristics for two different regions of a deep seismic reflection profile in northwestern Canada demonstrate that in both cases the points are not randomly distributed and that the point pattern distribution is different between the regions. The cluster effects for small point pair distances are stronger for the region of data where there is strong sedimentary layering than for the region where the layering is less distinct. As a result, it appears that future developments in point pattern analysis may provide a new tool for analysing spatial variations in reflection data.

We explore real telecommunication data describing the spatial geometrical structure of an urban region and we propose a model fitting procedure, where a given choice of different non-iterated and iterated tessellation models is considered and fitted to real data. This model fitting procedure is based on a comparison of distances between characteristics of sample data sets and characteristics of different tessellation models by utilizing a chosen metric. Examples of such characteristics are the mean length of the edge-set or the mean number of vertices per unit area. In particular, after a short review of a stochastic-geometric telecommunication model and a detailed description of the model fitting algorithm, we verify the algorithm by using simulated test data and subsequently apply the procedure to infrastructure data of Paris.

The keratin filament network is an important part of the cytoskeleton. It is involved in the regulation of shape and viscoelasticity of epithelial cells. The morphology of keratin networks depends on post-translational modifications of keratin monomers. In-vitro studies indicated that network characteristics, such as filament crosslink density, determines the biophysical properties of the filament network. This report presents a quantitative method for the morphological analysis of keratin filament networks. Visualization of filaments was based on prefixation extraction of epithelial cells and scanning electron microscopy (SEM). SEM images were processed by a skeletonization algorithm to obtain a graph structure that represents individual filaments as well as their connections. This method was applied to investigate the effects of transforming growth factor alpha (TGFalpha) on the morphology of keratin networks in pancreatic cancer cells. TGFalpha contributes to pancreatic cancer progression and activates signalling pathways phosphorylating keratin monomers. Using this new method, a significant alteration to the keratin network morphology could be detected in response to TGFalpha.

Efficient syntheses of 5-brominated and 5,5'-dibrominated 2,2'-bipyridines and 2,2'-bipyrimidines, useful for the preparation of metal-complexing molecular rods, have been developed. 5-Bromo-2,2'-bipyridine, 5-bromo-5'-n-butyl-2,2'-bipyridine, and 5-bromo-5'-n-hexyl-2,2'-bipyridine were obtained by Stille coupling of 2,5-dibromopyridine with 2-trimethylstannylpyridine or the requisite 5-alkyl-2-trimethylstannylpyridine, obtained via regioselective zincation of a 3-alkylpyridine.BF(3) complex in the less hindered of the two reactive positions with lithium di-tert-butyl-(2,2,6,6-tetramethylpiperidino)zincate. 5,5'-Dibromo-2,2'-bipyridine was obtained by the reductive symmetric coupling of 2,5-dibromopyridine with hexa-n-butyldistannane. The yields of these coupling reactions ranged from 70 to 90%. 5-Bromo- and 5,5'-dibromo-2,2'-bipyrimidines were obtained in yields of 30 and 15%, respectively, by bromination of 2,2'-bipyrimidine, prepared from 2-chloropyrimidine in 80% yield by an improved reductive symmetric coupling procedure.

Afatinib (BIBW 2992) is an ErbB-family blocker that irreversibly inhibits signaling from all relevant ErbB-family dimers. Afatinib has demonstrated preclinical activity in human epidermal growth factor receptor HER2 (ErbB2)-positive and triple-negative xenograft models of breast cancer, and clinical activity in phase I studies. This was a multicenter phase II study enrolling patients with HER2-negative metastatic breast cancer progressing following no more than three lines of chemotherapy. No prior epidermal growth factor receptor-targeted therapy was allowed. Patients received 50-mg afatinib once daily until disease progression. Tumor assessment was performed at every other 28-day treatment course. The primary endpoint was clinical benefit (CB) for ≥4 treatment courses in triple-negative (Cohort A) metastatic breast cancer (TNBC) and objective responses measured by Response Evaluation Criteria in Solid Tumors in patients with HER2-negative, estrogen receptor-positive, and/or progesterone receptor-positive breast cancer (Cohort B). Fifty patients received treatment, including 29 patients in Cohort A and 21 patients in Cohort B. No objective responses were observed in either cohort. Median progression-free survival was 7.4 and 7.7 weeks in Cohorts A and B, respectively. Three patients with TNBC had stable disease for ≥4 treatment courses, one of them for 12 courses (median 26.3 weeks; range 18.9-47.9 weeks). The most frequently observed afatinib-associated adverse events (AEs) were gastrointestinal and skin-related side effects, which were manageable by symptomatic treatment and dose reductions. Afatinib pharmacokinetics were comparable to those observed in previously reported phase I trials. In conclusion, afatinib had limited activity in HER2-negative breast cancer. AEs were generally manageable and mainly affected the skin and the gastrointestinal tract., Clinical Trial, Phase II, Journal Article, Multicenter Study, Research Support, Non-U.S. Gov't, SCOPUS: ar.j, info:eu-repo/semantics/published

Cell migration is an essential element in the immune response on the one hand and in cancer metastasis on the other hand. The architecture of the actin network in lamellipodia determines the elasticity of the leading edge and contributes to the regulation of migration. We have implemented a new method for the analysis of actin network morphology in the lamellipodia of B16F1 mouse melanoma cells. This method is based on fitting multi-layer geometrical models to electron microscopy images of lamellipodial actin networks. The chosen model and F-actin concentrations are thereby deterministic parameters. Using this approach, we identified distinct structural features of actin networks in lamellipodia. The mesh size which defines the elasticity of the lamellipodium was determined as 34 and 78?nm for a two-layer network at a total actin concentration of 9.6?mg?ml?1. These data lead to estimates of the low frequency elastic shear moduli which differ by more than a magnitude between the two layers. These findings indicate an anisotropic shear modulus of the lamellipodium with the stiffer layer being the dominant structure against deformations in the lamellipodial plane and the softer layer contributing significantly at lower indentations perpendicular to the lamellipodial plane. This combination creates a material that is optimal for pushing forward as well as squeezing through narrow spaces.

Point process characteristics like for example Ripley’s K-function, the L-function or Baddeley’s J-function are especially useful for cases of data with significant differences with respect to intensities. We will discuss two examples in the fields of cell biology and ecology were these methods can be applied. They have been chosen, because they demonstrate the wide range of applications for the described techniques and because both examples have specific interest- ing properties. While the point patterns regarded in the first application are three dimensional, the second application reveals planar point patterns having a vertically inhomogeneous structure.

Im Transformationsprozess der Wirtschaft in Ostdeutschland wurde die Industrieforschung besonders stark abgeschmolzen. Zudem erschwerten Phänomene der Marktunvollkommenheit im Bereich der wirtschaftsnahen Forschung und Entwicklung (FuE) und Innovation (Informationsdefizite und Unsicherheit, externe Effekte, Unteilbarkeiten) die Neuformierung des regionalen Innovationssystems. Der Bund und die neuen Länder haben deshalb zahlreiche Maßnahmen zur finanziellen Unterstützung des Neuaufbaus einer leistungsfähigen Industrieforschung ergriffen. Dabei ist generell umstritten, in welchem Umfang und mit welchen Instrumenten der Staat in die marktnahen FuE-Aktivitäten der privaten Wirtschaft eingreifen sollte. In diesem Beitrag wird ein Überblick über die Maßnahmen der staatlichen Förderung der industriellen FuE in Ostdeutschland im letzten Jahrzehnt gegeben. Ein Schwerpunkt ist die Darstellung der staatlichen Zuschüsse zu den FuE-Aufwendungen als Hauptform der Förderung. In der anschließenden Wirkungsanalyse dieser Förderung stehen zwei Fragen im Mittelpunkt: Wie hat sie auf die Entwicklung des FuE-Potentials der Industrie gewirkt? Welchen Beitrag leistet das FuE-Potential in den Unternehmen und den wirtschaftsnahen Forschungseinrichtungen der neuen Länder zur technologischen Leistungsfähigkeit der ostdeutschen Wirtschaft?

Abstract 3316 Background: Patients with refractory or relapsed AML have a poor prognosis and new treatments are needed for this patient population. While younger AML patients might benefit from intensive salvage treatments, a substantial number of elderly patients are considered ineligible for intensive treatment approaches. For these patients, repeated cycles of low-dose cytarabine (LD-Ara-C) are an accepted therapeutic option for palliative treatment. The serine/threonine kinase Polo-like kinase 1 (Plk1) controls several key steps in mitosis. BI 6727 is a first in class, highly selective and potent cell cycle kinase inhibitor targeting Plk1, and has demonstrated antiproliferative activity in multiple cell lines and animal models. Targeting Plk1 with BI 6727 results in cell cycle arrest in prometaphase (referred to as polo arrest) leading to eventual apoptosis. In a phase I dose escalation trial in patients with advanced solid tumors a favorable safety profile and encouraging antitumor activity was reported. BI 6727 has demonstrated a long terminal half life of 111 hours and a high volume of distribution suggesting excellent tissue distribution in patients. Here, we present preliminary results from the Phase I part of an ongoing Phase I/II study of BI 6727 in combination with LD-Ara-C in patients with relapsed or refractory AML considered ineligible for intensive treatment. Methods: This study follows a two stage design: the maximum tolerated dose (MTD) of BI 6727 in combination with fixed dose LD-Ara-C was evaluated in the Phase I dose escalation part of the trial following a 3+3 design with de-escalation. In a second ongoing treatment schedule the MTD of single agent BI 6727 is investigated, the MTD of single agent BI 6727 has not been reached yet. In the planned randomized Phase II part of the study, efficacy of BI 6727 plus LD-Ara-C will be compared to LD-Ara-C alone. BI 6727 was administered as a one hour intravenous infusion on days 1+15 every 28 days in combination with fixed dose LD-Ara-C (20 mg bid s.c). The BI 6727 starting dose was based on the MTD previously determined in solid tumor patients. Patients with no progression after the first cycle were allowed to continue treatment. Results: Patient characteristics were as follows: median age was 71 years (range 40 – 81); ECOG performance score 0: 9 pts; 1: 17 pts; 2: 5 pts. Increasing BI 6727 doses in combination with LD-Ara-C were evaluated in 31 patients (21 males, 10 females). Safety: Drug related adverse events (AEs) were reported in 17 of the 31 patients. The most frequent AEs reported (>5%) were: anemia and febrile neutropenia (each 9.7%), infections (pneumonia), decreased appetite and headache (each 6.5%). Dose-limiting toxicities (DLTs) were reported in 4 patients treated with BI 6727 + LD-Ara-C. DLTs as rated per protocol were: pneumonia, mucositis, hypersensitivity/allergic reaction and myocardial infarction. Based on the preliminary reports on DLTs the MTD for BI 6727 in combination with LD-Ara-C was determined. Preliminary response data of 28 patients with relapsed/refractory AML treated at different BI 6727 doses in combination with LD-Ara-C are available: 5 patients achieved a CRi or CR, 2 patients achieved a PR. Six patients had temporarily stable blood values (“no change” as best response). 10 patients suffered from progression during or at the end of the 1st treatment cycle, and 5 patients were ineligible for response assessment. An update of the phase I part of this trial with further details on patient/disease characteristics, safety and efficacy of BI 6727 in combination with LD-Ara-C will be reported at the meeting. Conclusion: Preliminary results indicate that BI 6727 in combination with LD-Ara-C is well tolerated in patients with relapsed/refractory AML ineligible for intensive treatment. The MTD of BI 6727 in combination with LD-Ara-C was determined. BI 6727 in combination with LD-Ara-C showed first signs of clinical activity in AML patients. Safety and efficacy of BI 6727 + LD-Ara-C will be further explored in the phase II part of the trial. Disclosures: Off Label Use: LD-Ara-C in combination with BI 6727 for treatment of patients with relapsed refractory AML ineligible for intensive treatment. Fleischer:Boehringer Ingelheim Pharma GmbH & Co KG: Employment. Taube:Boehringer Ingelheim Pharma GmbH & Co KG: Employment.

Background: BI 2536 is a potent and selective inhibitor of Plk-1, which plays a crucial role in the regulation of mitosis. Inhibition of Plk-1 leads to mitotic arrest and apoptosis. Therefore, Plk-1 inhibitors are currently in clinical testing as anti-proliferative agents in cancer patients. BI 2536, the first specific Plk-1 inhibitor in clinical testing, demonstrated strong anti-proliferative effects on AML cell lines in vitro and in in vivo models. To investigate target inhibition in the malignant cell, bone marrow samples from patients who participated in a Phase I/II study of BI 2536 single-agent therapy in elderly patients with relapsed or refractory AML were analyzed. Methods: Pharmacodynamic analyses including immunocytochemistry (ICC) and flow cytometry (FACS) of bone marrow (BM) were performed to examine cell morphology, phosphorylation of histone H3 (phospho-H3), and induction of apoptosis. Samples were acquired before and 24 h after the first administration of BI 2536. FACS analysis included propidium iodide (PI)-FACS to determine the percentage of cells residing in various cell cycle stages (G0/1-, S- and G2/M-phases) and Annexin V-Cy5-staining for apoptosis. Immunocytochemistry included staining for phosphorylated histone H3 and TUNEL assay for apoptosis. Results: At the time of analysis, data from 28 patients treated at doses in the range of 50 to 400 mg BI 2536 were available. BM taken after BI 2536 administration showed an increase of phospho-H3 positive cells as compared to baseline prior to treatment. There was a trend toward a positive correlation between phospho-H3 increase and increase in dosage of BI 2536 (p=0.16) when treatment at low doses (50 to 60 mg) of BI 2536 were compared to treatment at higher doses (100 to 400 mg). Furthermore, trends were observed that an increase of phospho-H3 is positively correlated with both a higher percentage of cells in G2/M and an increase in apoptotic cells. The typical morphology of cells in mitotic arrest could be demonstrated by ICC. Interestingly, when patients with progressive disease after one cycle (PD) were compared to patients with disease stabilization or response (nonPD), a statistically significant positive correlation between PD and increase in phospho-H3 compared to baseline was found (p=0.03). Also, there was a clear trend for an increase in the percentage of cells in G2/M phase and apoptosis in patients with PD compared to patients with nonPD. Preliminary evaluation of other disease characteristics including karyotype (normal vs complex), secondary AML, complete response in previous treatments, baseline value for blasts in the bone marrow or in the peripheral blood, did not reveal any signs of correlation with the clinical response to BI 2536 treatment. Conclusion: BI 2536 treatment increases the number of cells in G2/M phase (as detected by FACS analysis and phospho-H3 staining) and the number of apoptotic cells within 24 h after administration. In line with the clinical observation of rapid blast reduction both in the BM and the peripheral blood, these findings indicate that BI 2536 induces mitotic arrest and apoptosis of the malignant target cells in AML patients. The biological meaning of the correlation between the BM findings and the clinical response to BI 2536 is unclear, but if substantiated by more data, these results may suggest a predictive value of BM examinations for the response to BI 2536.

not Available.

NMR and x-ray anal. indicated that pyridazine deriv. I exists in a twist conformation. A ring inversion barrier of 91.5 kJ/mol was found for I.

Background A phase I study to assess the maximum tolerated dose (MTD) of a short course of afatinib in combination with docetaxel for the treatment of solid tumors. Methods Patients with advanced solid malignancies received docetaxel 75 mg/m(2) intravenously on day 1 and oral afatinib once daily on days 2-4, in 3-week treatment cycles. The afatinib dose was escalated in successive cohorts of 3-6 patients until dose-limiting toxicity (DLT). The MTD cohort was expanded to 13 patients. Pharmacokinetic parameters were assessed. Results Forty patients were treated. Afatinib doses were escalated to 160 mg/day in combination with 75 mg/m(2) docetaxel. Three patients had drug-related DLTs during cycle 1. The MTD was defined as 90 mg/day afatinib (days 2-4) with docetaxel 75 mg/m(2). The most frequent drug-related adverse events (all grades) were alopecia, diarrhea, stomatitis (all 50 %) and rash (40 %, all grade ≤2). Three patients had confirmed responses, two patients had unconfirmed responses and nine patients had durable stable disease >6 cycles. No pharmacokinetic interaction was observed. Conclusion Afatinib 90 mg administered for 3 days after docetaxel 75 mg/m(2) is the MTD for this treatment schedule and the recommended phase II/phase III dose. This combination showed anti-tumor activity in phase I, with a manageable adverse-event profile., Journal Article, SCOPUS: ar.j, info:eu-repo/semantics/published

Successful Transformations? contrasts the recent experience of economic development in Eastern Germany and the Czech Republic. It provides a comparative up-to-date account critically assessing the transition from central planning to a free market economy. The book highlights the very different paths that these two economies have taken. Eastern Germany has been absorbed almost entirely into the political and economic framework of West Germany. In contrast the Czech Republic – which is widely acclaimed to have made the speediest transition – has from the outset adopted an independent line.