Prognostischer Einfluss von persistierenden isolierten Tumorzellen im Knochenmark von Mammakarzinom- Patientinnen

Die Einschätzung der Prognose ist für die Therapie des Mammakarzinoms von großer Bedeutung und basiert heutzutage noch auf empirischen Daten. Disseminierte Tumorzellen im Knochenmark gelten als Ursprungsort für die Fernmetastasierung. Patientinnen mit hohem Rezidivrisiko können zum Zeitpunkt der Primärdiagnose durch den Nachweis disseminierter Tumorzellen im Knochenmark individuell identifiziert werden. Mit konventionellen Screening- Methoden können persistierende isolierte Tumorzellen im Knochenmark nicht entdeckt und nicht im Verlauf beobachtet werden. Die immunzytochemische Untersuchung des Knochenmarks könnte eine Möglichkeit sein, um auch nach Resektion des Primärtumors bei krankheitsfreien Patientinnen noch eine Einschätzung der weiteren Prognose vorzunehmen. Daher wurde diese Studie initiiert, um den prognostischen Einfluss von persistierenden isolierten Tumorzellen im Knochenmark von Patientinnen mit primärem Mammakarzinom zu untersuchen. Bei 228 Patientinnen mit primärem Mammakarzinom (pT1-2 pN0-3 M0 R0) wurden Nachpunktionen vorgenommen und der klinische Verlauf dokumentiert. Der Nachweis isolierter Tumorzellen im Knochenmarkaspirat erfolgte durch immunzytochemische Färbung mit dem Pan-Zytokeratin-Antikörper A45-B/B3 (Micromet, München). Das mediane Zeitintervall zwischen Erstdiagnose und Nachpunktion betrug 21,3 Monate. Die Nachbeobachtungszeit betrug im Median 49,8 Monate. Insgesamt persistierten isolierte disseminierte Tumorzellen bei 29 (12,7%) der 228 Patientinnen. Das krankheitsfreie Überleben war signifikant mit dem Knochenmarkstatus bei Nachpunktion assoziiert. Das mittlere krankheitsfreie Überleben von Patientinnen mit einem negativen Knochenmarkstatus betrug 149,7 Monate. Bei Patientinnen mit persistierenden isolierten Tumorzellen im Knochenmark betrug das mittlere krankheitsfreie Überleben 86,5 Monate und Prognostischer Einfluss von persistierenden isolierten Tumorzellen im Knochenmark von Mammakarzinom- Patientinnen war signifikant verkürzt (p=0,0003; Log- Rank- Test). Bei der Untersuchung des Zusammenhangs zwischen Knochenmarkbefund und Zeitraum bis zum Auftreten von Fernmetastasen zeigte sich, dass ein Auftreten von Fernmetastasen bei Patientinnen mit persistierenden isolierten Tumorzellen im Knochenmark signifikant (p=0,00001; Chi2- Test) häufiger war. Im Vergleich traten bei Patientinnen mit einem positiven Nachpunktionsergebnis im Mittel nach 89,8 Monate Fernmetastasen auf. Es zeigte sich, dass isolierte persistierende disseminierte Tumorzellen im Knochenmark einen unabhängigen signifikanten (p< 0,0001; Log- Rank- Test) prognostischen Faktor für einen verkürzten Zeitraum bis zum Auftreten eines Krankheitsrückfalls darstellen. Der prognostische Wert persistierender Tumorzellen war bei einem Nachpunktionszeitraum von 25 bis 42 Monaten nach Primärdiagnose signifikant (p=0,013; Log- Rank- Test). Die multivariate Analyse bestätigte den Knochenmarkstatus bei Nachpunktion als signifikanten unabhängigen Prognosefaktor für das Gesamtüberleben (p=0,002). Schlussfolgernd ist die Knochenmarkpunktion im rezidivfreien Intervall von prognostischer Bedeutung für das rezidivfreie und Gesamtüberleben von Mammakarzinom-Patientinnen. Da Patientinnen mit isolierten persistierenden Tumorzellen im Knochenmark eine ungünstige Prognose haben, könnte der Knochenmarknachpunktions- Status zukünftig eine Indikation zur sekundären adjuvanten Therapie darstellen. Der therapeutische Benefit einer solchen sekundäradjuvanten Therapieintervention muss in prospektiven Studien untersucht werden

Numerical Analysis of Fluid Flow and Heat Transfer in Wavy and Hybrid-Slit-Wavy (HSW) Fin-and-Tube Heat Exchangers

This numerical study pertains to characterizing flow and heat transfer interactions for an interrupted fin design with wavy profile in compact tube-and-fin heat exchanger. Although designs with similar concept is prevalent in the HVAC&R industry not much literature exists on the subject combining wavy fins with periodic interruptions. Presently sinusoidal wavy fin is combined with slit fins to investigate thermal-hydraulic performance relative to an un-interrupted fin design. This fin is referred to as Hybrid Slit Wavy (HSW) fin in this work. Commercial Computational Fluid Dynamics (CFD) software is used for 3D numerical solution of the complete Navier–Stokes and energy equations in the heat exchanger to study flow physics and predict performance. The modeling approach is first validated with available test data from the literature on a wavy (Herringbone profile) fin heat exchanger. The predicted friction factor was within 12% and the Colburn j-factor was within 7% of the reported test data over a Reynolds number range of 350-6500. In the case of the HSW fin it was found that the air-side heat transfer is enhanced by about 20-39% relative to the baseline un-interrupted fin with an associated pressure drop penalty of 20-38%. The area goodness factors of the HSW fins are up to 4 % higher compared to the wavy fins at various operating conditions indicative of favorable trade-off. It is further established that the local flow pattern including boundary layer modifications, wake structures and enhanced flow mixing correlates strongly with local Nusselt number distribution

Adhesion of Leukocytes to Cerebral Venules Precedes Neuronal Cell Death and Is Sufficient to Trigger Tissue Damage After Cerebral Ischemia

BackgroundLeukocytes contribute to tissue damage after cerebral ischemia;however, the mechanisms underlying this process are still unclear. This study investigates the temporal and spatial relationship between vascular leukocyte recruitment and tissue damage and aims to uncover which step of the leukocyte recruitment cascade is involved in ischemic brain injury. MethodsMale wild-type, ICAM-1-deficient, anti-CD18 antibody treated, or selectin-deficient [fucusyltransferase (FucT IV/VII-/-)] mice were subjected to 60 min of middle cerebral artery occlusion (MCAo). The interaction between leukocytes and the cerebrovascular endothelium was quantified by in vivo fluorescence microscopy up to 15 h thereafter. Temporal dynamics of neuronal cell death and leukocyte migration were assessed at the same time points and in the same tissue volume by histology. ResultsIn wild-type mice, leukocytes started to firmly adhere to the wall of pial postcapillary venules two hours after reperfusion. Three hours later, neuronal loss started and 13 h later, leukocytes transmigrated into brain tissue. Loss of selectin function did not influence this process. Application of an anti-CD18 antibody or genetic deletion of ICAM-1, however, significantly reduced tight adhesion of leukocytes to the cerebrovascular endothelium (-60%;p < 0.01) and increased the number of viable neurons in the ischemic penumbra by 5-fold (p < 0.01);the number of intraparenchymal leukocytes was not affected. ConclusionsOur findings suggest that ischemia triggers only a transient adhesion of leukocytes to the venous endothelium and that inhibition of this process is sufficient to partly prevent ischemic tissue damage

Neurovascular Reactivity in the Aging Mouse Brain Assessed by Laser Speckle Contrast Imaging and 2-Photon Microscopy: Quantification by an Investigator-Independent Analysis Tool

The brain has a high energy demand but little to no energy stores. Therefore, proper brain function relies on the delivery of glucose and oxygen by the cerebral vasculature. The regulation of cerebral blood flow (CBF) occurs at the level of the cerebral capillaries and is driven by a fast and efficient crosstalk between neurons and vessels, a process termed neurovascular coupling (NVC). Experimentally NVC is mainly triggered by sensory stimulation and assessed by measuring either CBF by laser Doppler fluxmetry, laser speckle contrast imaging (LSCI), intrinsic optical imaging, BOLD fMRI, near infrared spectroscopy (NIRS) or functional ultrasound imaging (fUS). Since these techniques have relatively low spatial resolution, diameters of cerebral vessels are mainly assessed by 2-photon microscopy (2-PM). Results of studies on NVC rely on stable animal physiology, high-quality data acquisition, and unbiased data analysis, criteria, which are not easy to achieve. In the current study, we assessed NVC using two different imaging modalities, i.e., LSCI and 2-PM, and analyzed our data using an investigator-independent Matlab-based analysis tool, after manually defining the area of analysis in LSCI and vessels to measure in 2-PM. By investigating NVC in 6–8 weeks, 1-, and 2-year-old mice, we found that NVC was maximal in 1-year old mice and was significantly reduced in aged mice. These findings suggest that NVC is differently affected during the aging process. Most interestingly, specifically pial arterioles, seem to be distinctly affected by the aging. The main finding of our study is that the automated analysis tool works very efficiently in terms of time and accuracy. In fact, the tool reduces the analysis time of one animal from approximately 23 h to about 2 s while basically making no mistakes. In summary, we developed an experimental workflow, which allows us to reliably measure NVC with high spatial and temporal resolution in young and aged mice and to analyze these data in an investigator-independent manner

Current and future water balance for coupled human-natural systems – Insights from a glacierized catchment in Peru

Study region Santa River basin, Peru. Study focus In the Andes of Peru, climate change and socio-economic development are expected to jeopardize future water availability. However, little is known about the interplay of multiple climatic and non-climatic stressors and related processes driving water resource changes. We developed an integrated model that analyzes different trajectories of water availability including hydro-climatic (water supply) and socio-economic (water demand) variables with consistent multi-descriptor future scenarios until 2050. New hydrological insights for the region At the lower-basin outflow of Condorcerro, mean annual water availability is projected to increase by 10% ± 12% by 2050. This gain is mainly driven by an increase in annual precipitation amounts of about 14% (RCP2.6) and 18% (RCP8.5), respectively, which was computed using a global climate multi-model ensemble. In contrast, mean dry-season water availability is projected to substantially decrease by 33% and 36% ( ± 24%) by 2050, for RCP2.6 and RCP8.5, respectively. This decline is driven by a combination of diminishing glacier discharge and increasing water demand both of which adopt a major role in the absence of considerable precipitation inputs. These seasonal differences highlight the need to adequately consider spatiotemporal scales within multi-scenario water balance models to support local decision-making. Our results elucidate the need for improvements in water management and infrastructure to counteract diminishing dry-season water availability and to reduce future risks of water scarcity

User-Centric Future Internet and Telecommunication Services

This paper analyses the current service creation trends in telco and Web worlds, showing how they are converging towards a future Internet of usercentric services embracing typical telco capabilities. The OPUCE platform is presented as the next step towards this integrated, user-centric future: a platform which offers intuitive tools for graphical service creation aimed at individuals with no specific skills in computer science or programming and a serviceoriented execution environment capable of a seamless interoperation of Web Services and telco applications based on operator-owned infrastructure. The OPUCE platform is compared to existing mashup creation tools to show its advantages and how is compared to existing mashup creation tools to show its advantages and how it could be used to implement a converged and open service marketplace for the Future Internet

A User-centric Mobile Service Creation Approach Converging Telco and IT Services

While new competitors are threatening the traditional business models of Telecommunications operators by providing their services directly to the customer, usercentric service creation paradigm brings new opportunities for operators to deliver diverse, attractive, and profitable services directly to the end-user. This paper discusses the service creation model, architecture and implementation in the European Union sponsored research project OPUCE (Open Platform for User-Centric Service Creation and Execution), which aims at enabling end-users to use their smart mobile devices for both creating and consuming personalized services