Tumor angiogenesis and anti-angiogenic therapy in malignant gliomas revisited

The cellular and molecular mechanisms of tumor angiogenesis and its prospects for anti-angiogenic cancer therapy are major issues in almost all current concepts of both cancer biology and targeted cancer therapy. Currently, (1) sprouting angiogenesis, (2) vascular co-option, (3) vascular intussusception, (4) vasculogenic mimicry, (5) bone marrow-derived vasculogenesis, (6) cancer stem-like cell-derived vasculogenesis and (7) myeloid cell-driven angiogenesis are all considered to contribute to tumor angiogenesis. Many of these processes have been described in developmental angiogenesis; however, the relative contribution and relevance of these in human brain cancer remain unclear. Preclinical tumor models support a role for sprouting angiogenesis, vascular co-option and myeloid cell-derived angiogenesis in glioma vascularization, whereas a role for the other four mechanisms remains controversial and rather enigmatic. The anti-angiogenesis drug Avastin (Bevacizumab), which targets VEGF, has become one of the most popular cancer drugs in the world. Anti-angiogenic therapy may lead to vascular normalization and as such facilitate conventional cytotoxic chemotherapy. However, preclinical and clinical studies suggest that anti-VEGF therapy using bevacizumab may also lead to a pro-migratory phenotype in therapy resistant glioblastomas and thus actively promote tumor invasion and recurrent tumor growth. This review focusses on (1) mechanisms of tumor angiogenesis in human malignant glioma that are of particular relevance for targeted therapy and (2) controversial issues in tumor angiogenesis such as cancer stem-like cell-derived vasculogenesis and bone-marrow-derived vasculogenesis

“Zur Neuen Welt” — Towards the New World. Ludwig Mies and his Architectural Youth in Aachen

Ludwig Mies van der Rohe's personal and professional connections to his hometown Aachen in Germany are mostly unknown today. Through the analysis of both old and new written and graphic sources, the authors give an insight into Mies van der Rohe's lifelong bond to his hometown. In the personal friendships, his friends Ferdinand Goebbels and Franz Dominick play a key role. Furthermore, the paper presents previously unknown buildings that young Mies was working on in the office of Albert Schneiders around 1905. One of the buildings, the house “Zur Neuen Welt” for client Joseph Oeben, is still standing and represents a lively example of the stylistic search in architecture after the turn of the millennium, and an early step towards Mies van der Rohe's architectural maturity

Protoplanetary Disk Masses from Stars to Brown Dwarfs

We present SCUBA-2 850um observations for 7 very low mass stars (VLMS) and brown dwarfs (BDs): 3 in Taurus, 4 in the TWA, and all classical T Tauri (cTT) analogs. We detect 2 of the 3 Taurus disks, but none of the TWA ones. Our 3sigma limits correspond to a dust mass of 1.2 MEarth in Taurus and a mere 0.2 MEarth in the TWA (3--10x deeper than previous work). We combine our data with other sub-mm/mm surveys of Taurus, rho Oph and the TWA to investigate trends in disk mass and grain growth during the cTT phase. We find : (1) The minimum disk outer radius required to explain the upper envelope of sub-mm/mm fluxes is 100 AU for intermediate-mass stars, solar-types and VLMS, and 20 AU for BDs. (2) While the upper envelope of disk masses increases with Mstar from BDs to VLMS to solar-types, no increase is seen from solar-type to intermediate-mass stars. We propose this is due to enhanced photoevaporation around intermediate masses. (3) Many disks around Taurus and rho Oph intermediate-mass and solar-type stars evince an opacity index beta of 0--1, indicating large grains. Of the only four VLMS/BDs in these regions with multi-wavelength data, three are consistent with large grains, though optically thick disks are not ruled out. (4) For the TWA VLMS (TWA 30A, B), combining our fluxes with Mdot and ages suggests substantial grain growth by 10 Myr. The degree of grain growth in the TWA BDs (2M1207A, SSPM1102) remains largely unknown. (5) A Bayesian analysis shows that mean(log[Mdisk/Mstar]) = -2.4, roughly constant all the way from intermediate-mass stars to VLMS/BDs, and (6) the disk mass in close solar-type Taurus binaries is significantly lower than in singles (by a factor of 10), while that in wide solar-type Taurus binaries is closer to that in singles (lower by a factor of 3). (7) We discuss the implications for planet formation, and for the dependence of Mdot on Mstar.Comment: ApJ, accepted (in press

Order picking with multiple pickers and due dates: Simultaneous solution of order batching, batch assignment and sequencing, and picker routing problems

In manual picker-to-parts order picking systems of the kind considered in this article, human operators (order pickers) walk or ride through the warehouse, retrieving items from their storage location in order to satisfy a given demand specified by customer orders. Each customer order is characterized by a certain due date until which all requested items included in the order are to be retrieved and brought to the depot. For the actual picking process, customer orders may be grouped (batched) into more substantial picking orders (batches). The items of a picking order are then collected on a picker tour through the warehouse. Thus, the picking process of each customer order in the batch is only completed when the picker returns to the depot after the last item of the batch has been picked. Whether and to which extend due dates are violated (tardiness) depends on how the customer orders are batched, how the batches are assigned to order pickers, how the assigned batches are sequenced and how the pickers are routed through the warehouse. Existing literature has only treated special aspects of this problem (i.e. the batching problem or the routing problem) so far. In this paper, for the first time, an approach is proposed which considers all aspects simultaneously. A mathematical model of the problem is introduced that allows for solving small problem instances in reasonable computing times. For larger instances, a variable neighborhood descent (VND) algorithm is presented which includes various neighborhood structures regarding the batching and sequencing problem. Furthermore, two sophisticated routing algorithms are integrated into the VND algorithm. By means of numerical experiments, it is shown that this algorithm provides solutions of excellent quality

Multitrip vehicle routing with delivery options: a data-driven application to the parcel industry

To make the last mile of parcel delivery more efficient, service providers offer an increasing number of modes of delivery as alternatives to the traditional and often cost-intensive home delivery service. Parcel lockers and pickup stations can be utilized to reduce the number of stops and avoid costly detours. To design smart delivery networks, service providers must evaluate different business models. In this context, a multitrip vehicle routing problem with delivery options and location-dependent costs arises. We present a data-driven framework to evaluate alternative delivery strategies, formulate a corresponding model and solve the problem heuristically using adaptive large neighborhood search. By examining large, real-life instances from a major European parcel service, we determine the potential and benefits of different delivery options. Specifically, we show that delivery costs can be mitigated by consolidating orders in pickup stations and illustrate how pricing can be applied to steer customer demand toward profitable, eco-friendly products

Gemeindesteuern der Zinsbereinigten Gewinnsteuer

Ein rationales Steuersystem sollte sich durch Finanzierungs-, Investitions- und Rechtsformneutralität auszeichnen und das Wirtschaftswachstum möglichst nicht negativ beeinträchtigen. Ferner muss eine Steuererhebung seitens der Finanzverwaltung und eine Steuerbefolgung durch die Steuerpflichtigen unter administrativ vertretbarem Aufwand möglich sein. Das geltende deutsche Steuersystem vermag diese Anforderungen auch nach der jüngsten Unternehmensteuerreform von 2008 nicht zu erfüllen. Mit dem Reformvorschlag 'Zinsbereinigte Gewinnsteuer' (ZGS) sollen diese Mängel beseitigt werden. Gemeindesteuern sind ein wichtiger Bestandteil des Steuersystems und bedürfen der besonderen Beachtung im Rahmen einer konsistenten Steuerreform. Insbesondere dürfen kommunale Steuern nicht die ökonomische Wirkung der föderalen konterkarieren. Die Reform der Gemeindefinanzierung wird hier vor dem Hintergrund und im Kontext der Reform der föderalen Ertragssteuern behandelt. Die ertragssteuerliche Umsetzung der ZGS bildet dabei die Grundlage für die Implementierung ihrer Gemeindesteuern. Zur Gemeindefinanzierung aus Steuermitteln sieht der Reformvorschlag ZGS vier Hauptsäulen vor. Eine betriebsstättenbezogene kommunale Gewinnsteuer mit zinsbereinigter Bemessungsgrundlage bildet die erste zentrale Säule. Sie wird von einer an der Einkommensteuer anknüpfenden kommunalen Bürgersteuer flankiert, die den Wohnortgemeinden zugute kommt. Zur Deckung von Finanzierungslücken wird ein neuer Anteil an der Umsatzsteuer eingeführt, der den einzelnen Gemeinden nach Maßgabe eines Verteilungsschlüssels zugewiesen wird. Eine vierte Säule der Gemeindefinanzierung stellt eine reformierte Grundsteuer dar. Teil 1 dieser Arbeit beschreibt die ZGS zunächst in ihren Grundzügen. Vor dem Hintergund der Kriterien für ein rationales kommunales Steuersystem wird die Gemeindeebene des Reformvoschlages entwickelt. Die Umsetzung der kommunalen Gewinnsteuer erfolgt auf der Basis der existierenden Gewerbesteuer, die zu einer Gemeindewirtschaftssteuer fortentwickelt wird. Auf systematisch notwendige Änderungen in der Bemessungsgrundlage wird dabei detailliert eingegangen. Die kommunale Bürgersteuer wird bezüglich ihrer Bemessungsgrundlage und Tarifstruktur konzeptionell beschrieben. Merkmale eines Verteilungsschlüssels für den neuen kommunalen Anteil an der Umsatzsteuer werden entwickelt und ökonomisch begründet. Ferner wird auf die Sinnhaftigkeit einer revitalisierten Grundsteuer als Bestandteil des kommunalen Steuersystems hingewiesen. Teil 2 beinhaltet Rechtsgrundlagen in Form von Änderungsgesetzen. Zwecks besserer Lesbarkeit werden außerdem die geänderten Rechtsnormen im Kontext des jeweiligen vollständigen Gesetzes abgedruckt. Die steuerrechtliche Implementierung der ZGS erfolgt für die kommunale Gewinnsteuer und den Verteilungsschlüssel des kommunalen Anteils an der Umsatzsteuer. Noch nicht Gegenstand der gesetzlichen Umsetzung sind die kommunale Bürgersteuer und die revitalisierte Grundsteuer.Gemeindesteuerreform, Rechtsgrundlagen, Zinsbereinigung

Integrated Order Picking and Vehicle Routing with Due Dates

Supermarkets typically order their goods from a centrally located distribution center (warehouse). Each order that the warehouse receives is characterized by the requested items, the location of the respective supermarket and a due date by which the items have to be delivered. For processing an order, a human operator (order picker) retrieves the requested items from their storage locations in the warehouse first. The items are then available for shipment and loaded on the vehicle which performs the tour including the respective location of the supermarket. Whether and to which extent a due date is violated (tardiness) depends on the composition of the tours, the corresponding routes and the start dates of the tours (vehicle routing subproblem). The start date of a tour, however, is also affected by the assignment of orders to pickers and the sequence according to which the orders are processed by the pickers (order picking subproblem). Although both subproblems are closely interconnected, they have not been considered simultaneously in the literature so far. In this paper, an iterated local search algorithm is designed for the simultaneous solution of the subproblems. By means of extensive numerical experiments, it is shown that the proposed approach is able to generate high-quality solutions even for large instances. Furthermore, the economic benefits of an integrated solution are investigated. Problem classes are identified, where the sequential solution of the subproblems leads to acceptable results, and it is pointed out in which cases an integrated solution is inevitable

A note on the Zassenhaus product formula

We provide a simple method for the calculation of the terms c_n in the Zassenhaus product $e^{a+b}=e^a e^b \prod_{n=2}^{\infty} e^{c_n}$ for non-commuting a and b. This method has been implemented in a computer program. Furthermore, we formulate a conjecture on how to translate these results into nested commutators. This conjecture was checked up to order n=17 using a computer

Effects of mining activities on fish communities and food web dynamics in a lowland river

Fish communities of streams and rivers might be substantially subsidized by terrestrial insects that fall into the water. Although such animal‐mediated fluxes are increasingly recognized, little is known about how anthropogenic perturbations may influence the strength of such exchanges. Intense land use, such as lignite mining, may impact a river ecosystem due to the flocculation of iron (III) oxides, thus altering food web dynamics. We compared sections of the Spree River in North‐East Germany that were greatly influenced by iron oxides with sections located downstream of a dam where passive remediation technologies are applied. Compared to locations downstream of the dam, the abundance of benthic macroinvertebrates at locations of high iron concentrations upstream of the dam was significantly reduced. Similarly, catch per unit effort of all fish was significantly higher in locations downstream of the dam compared to locations upstream of the dam, and the condition of juvenile and adult piscivorous pike Esox lucius was significantly lower in sections of high iron concentrations. Using an estimate of short‐term (i.e., metabarcoding of the gut content) as well as longer‐term (i.e., hydrogen stable isotopes) resource use, we could demonstrate that the three most abundant fish species, perch Perca fluviatilis, roach Rutilus rutilus, and bleak Alburnus alburnus, received higher contributions of terrestrial insects to their diet at locations of high iron concentration. In summary, lotic food webs upstream and downstream of the dam greatly differed in the overall structure with respect to the energy available for the highest tropic levels and the contribution of terrestrial insects to the diet of omnivorous fish. Therefore, human‐induced environmental perturbations, such as river damming and mining activities, represent strong pressures that can alter the flow of energy between aquatic and terrestrial systems, indicating a broad impact on the landscape level.Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659Fischereiabgabe Brandenburg, Ministerium für Landwirtschaft, Umwelt und Klimaschutz des Landes BrandenburgPeer Reviewe

A Spitzer Search For Planetary-Mass Brown Dwarfs With Circumstellar Disks: Candidate Selection

We report on initial results from a Spitzer program to search for very low-mass brown dwarfs in Ophiuchus. This program is an extension of an earlier study by Allers et al. which had resulted in an extraordinary success rate, 18 confirmed out of 19 candidates. Their program combined near-infrared and Spitzer photom- etry to identify objects with very cool photospheres together with circumstellar disk emission to indicate youth. Our new program has obtained deep IRAC pho- tometry of a 0.5 deg2 field that was part of the original Allers et al. study. We report 18 new candidates whose luminosities extend down to 10-4 L\cdot which sug- gests masses down to ~ 2 MJ if confirmed. We describe our selection techniques, likely contamination issues, and follow-on photometry and spectroscopy that are in progress