Tumor VEGF:VEGFR2 autocrine feed-forward loop triggers angiogenesis in lung cancer

The molecular mechanisms that control the balance between antiangiogenic and proangiogenic factors and initiate the angiogenic switch in tumors remain poorly defined. By combining chemical genetics with multimodal imaging, we have identified an autocrine feed-forward loop in tumor cells in which tumor-derived VEGF stimulates VEGF production via VEGFR2-dependent activation of mTOR, substantially amplifying the initial proangiogenic signal. Disruption of this feed-forward loop by chemical perturbation or knockdown of VEGFR2 in tumor cells dramatically inhibited production of VEGF in vitro and in vivo. This disruption was sufficient to prevent tumor growth in vivo. In patients with lung cancer, we found that this VEGF:VEGFR2 feed-forward loop was active, as the level of VEGF/VEGFR2 binding in tumor cells was highly correlated to tumor angiogenesis. We further demonstrated that inhibition of tumor cell VEGFR2 induces feedback activation of the IRS/MAPK signaling cascade. Most strikingly, combined pharmacological inhibition of VEGFR2 (ZD6474) and MEK (PD0325901) in tumor cells resulted in dramatic tumor shrinkage, whereas monotherapy only modestly slowed tumor growth. Thus, a tumor cell-autonomous VEGF:VEGFR2 feed-forward loop provides signal amplification required for the establishment of fully angiogenic tumors in lung cancer. Interrupting this feed-forward loop switches tumor cells from an angiogenic to a proliferative phenotype that sensitizes tumor cells to MAPK inhibition

Do business angels alter the risk-return equation in early stage investments? Business angels as seen by venture capitalists in the German speaking countries

Venture capitalists in German-speaking countries do not value the contribution of business angels in co-invested deals. Business angels do not reduce the risk perceived by venture capitalists in early-stage deals, even if the business angels have what venture capitalists regard as an ideal profile. Venture capitalists also refute that deals with business angels typically generate higher internal rates of return than deals without business angels.Venture capital; Business Angels;

Die Korrelation des Serummarkers S100B und des intraoperativen neurophysiologischen Monitorings mit dem klinischen Verlauf bei intraduralen Tumoren / vorgelegt von Charlotte Luise Heukamp

In der vorliegenden prospektiven Studie in der neurochirurgischen Klinik an der Johann Wolfgang Goethe-Universität in Frankfurt am Main wurden Oktober 2001 bis August 2006 dreiunddreißig Patienten mit intraduralen Raumforderungen der zervikalen und thorakalen Wirbelsäule unter Betrachtung eines möglichen prädiktiven Wertes der Serumkonzentration des Gliaproteins S100B und des intraoperativen Monitorings untersucht. Bei jedem Patienten erfolgte das intraoperative Monitoring mittels MEPs und SEPs, außerdem wurde prä- und mehrfach postoperativ die S100B-Serumkonzentration bestimmt. Anschließend wurden die Patienten mindestens 1 Jahr nach dem Eingriff in Bezug auf die noch bestehenden körperlichen Folgen sowie auch die Einschränkungen im alltäglichen Leben und im psychischen Wohlbefinden untersucht. Der Zusammenhang zwischen dem neurologischen Langzeitoutcome, den Teilergebnissen im intraoperativen Monitoring und im postoperativen S100B-Verlauf zeigte sich deutlich und war statistisch signifikant. Die gemeinsame Betrachtung der Serumkonzentration des Gliaproteins und des IOM unterstrich diese Ergebnisse nochmals, die Spezifität für ein gutes Outcome bei unkompliziertem Monitoring und ausbleibenden Anstieg des S100B lag zum Beispiel bei 100%. Auch in der Befragung zum alltäglichen Leben anhand des SF-36 zeigte sich ein klarer Zusammenhang zwischen dem klinischen Outcome und den subjektiv aus Patientensicht geschilderten Problemen in der Bewältigung des Alltags. Interessanterweise korrelierte aber die psychische Summenskala des Scores nicht mit dem körperlichen Befund. Die Gruppe des schlechten Outcomes zeigte ein besseres psychisches Wohlbefinden als die Gruppe des guten Outcomes, die aber mit der Normstichprobe vergleichbare Ergebnisse erzielte

Web-based database for the management of tissue specimens in a transregional histological research facility

BACKGROUND: In the setting of a histological research core facility sample tracking and project specific archiving of tissue specimens and communication of related data is of central importance. DESCRIPTION: Over a 24-month period 10 laboratories from two transregional research centers submitted in excess of 3000 tissue samples for histological processing and evaluation to our core facility. A web based database was set up to overcome the logistical problem of managing samples with inconsistent, duplicate and missing labels and to allow for efficient sample tracking, archiving and communication with the collaborating research laboratories. The database allows the users to remotely generate unique sample identifiers and enter sample annotation prior to sample processing. Furthermore the database facilitates communication about experimental set-up results and media files such as histological images. CONCLUSION: Our newly constructed web based portal is an important tool for the management of research samples of our histological core facility and facilitates significantly interdisciplinary and transregional research. It is freely available for scientific use

Impact of Cyclonic Wind Anomalies Caused by Massive Winter Sea Ice Retreat in the Barents Sea on Atlantic Water Transport Toward the Arctic: A Model Study

The Arctic is warming much faster than the global average. This is known as Arctic Amplification and is caused by feedbacks in the local climate system. In this study, we explore a previously proposed hypothesis that an associated wind feedback in the Barents Sea could play an important role by increasing the warm water inflow into the Barents Sea. We find that the strong recent decrease in Barents Sea winter sea ice cover causes enhanced ocean-atmosphere heat flux and a local air temperature increase, thus a reduction in sea level pressure and a local cyclonic wind anomaly with eastward winds in the Barents Sea Opening. By investigating various reanalysis products and performing high-resolution perturbation experiments with the ocean and sea ice model FESOM2.1, we studied the impact of cyclonic atmospheric circulation changes on the warm Atlantic Water import into the Arctic via the Barents Sea and Fram Strait. We found that the observed wind changes do not significantly affect the warm water transport into the Barents Sea, which rejects the wind-feedback hypothesis. At the same time, the cyclonic wind anomalies in the Barents Sea increase the amount of Atlantic Water recirculating westwards in Fram Strait by a downslope shift of the West Spitsbergen Current, and thus reduce Atlantic Water reaching the Arctic basin via Fram Strait. The resulting warm-water anomaly in the Greenland Sea Gyre drives a local anticyclonic circulation anomaly

An elevated turbulent mixing event caused by a near-inertial wave in the mixed layer

Between 2005 and 2016, an extensive shipboard and autonomous microstructure measurement program was carried out in the proximity of PIRATA sites in the central and northeastern tropical Atlantic. The data reveal regional variability of upper ocean mixing processes from diurnal to seasonal time scales. Here, we discuss an elevated turbulent mixing event below the mixed layer caused by surface near-inertial waves (NIWs) and address the impact of these mixing events on the mixed layer heat balance at the PIRATA site at 11.5°N, 23°W. Altogether, microstructure data at this site was collected during 8 different cruises. During one incident, sampling was conducted during the presence of an elevated NIW. Velocities associated with the NIW were above 0.6ms-1 in the mixed layer and decreased to near zero below the stratification maximum at 30m depth. Mixing during the presence of the NIW was strongly elevated and dissipation rates of turbulent kinetic energy exceeded 1x10-5m2s-3 in the stratified region below the mixed layer in some profiles. Associated cooling of the sea surface temperature was also elevated. Diapycnal heat flux was above 140Wm-2 10m below the mixed layer and more than 300Wm-2 in the region 5m below the mixed layer. Near-inertial wind stress magnitude (NIWSM) during the period war particularly high. Wind energy flux to NIWs from a slab ocean model is used to estimate the frequency of the occurrence of the elevated NIW ocean velocity

BET bromodomain protein inhibition is a therapeutic option for medulloblastoma

Medulloblastoma is the most common malignant brain tumor of childhood, and represents a significant clinical challenge in pediatric oncology, since overall survival currently remains under 70%. Patients with tumors overexpressing MYC or harboring a MYC oncogene amplification have an extremely poor prognosis. Pharmacologically inhibiting MYC expression may, thus, have clinical utility given its pathogenetic role in medulloblastoma. Recent studies using the selective small molecule BET inhibitor, JQ1, have identified BET bromodomain proteins, especially BRD4, as epigenetic regulatory factors for MYC and its targets. Targeting MYC expression by BET inhibition resulted in antitumoral effects in various cancers. Our aim here was to evaluate the efficacy of JQ1 against preclinical models for high-risk MYC-driven medulloblastoma. Treatment of medulloblastoma cell lines with JQ1 significantly reduced cell proliferation and preferentially induced apoptosis in cells expressing high levels of MYC. JQ1 treatment of medulloblastoma cell lines downregulated MYC expression and resulted in a transcriptional deregulation of MYC targets, and also significantly altered expression of genes involved in cell cycle progression and p53 signalling. JQ1 treatment prolonged the survival of mice harboring medulloblastoma xenografts and reduced the tumor burden in these mice. Our preclinical data provide evidence to pursue testing BET inhibitors, such as JQ1, as molecular targeted therapeutic options for patients with high-risk medulloblastomas overexpressing MYC or harboring MYC amplifications

Chemomechanics of calcium leaching of cement-based materials at different scales : the role of CH-dissolution and C-S-H degradation on strength and durability performance of materials and structures

Thesis (Ph. D .)--Massachusetts Institute of Technology, Dept. of Civil and Environmental Engineering, 2003.Includes bibliographical references (p. 327-341).Calcium leaching is a durability threat for cement-based materials employed in critical infrastructures, such as Nuclear Waste Storage Systems. This thesis presents a comprehensive study of the material and structural consequences of calcium leaching on the strength and deformation behavior of cementitious materials. Starting from a three-level microstructural division of the heterogeneous microstructure of cement-based materials, a series of experimental and theoretical investigations is conducted leading to the development of a novel constitutive model and model-based simulations of the long-term mechanical performance of concrete structures subjected to calcium leaching. A chemically accelerated leaching device is developed using an ammonium nitrate solution to obtain asymptotically leached specimens in short times. An acceleration rate of 300 compared to natural leaching is obtained. The strength domain of leached cement pastes and mortars is evaluated through triaxial compression tests and uniaxial tension tests, revealing an important strength loss and an increased pressure sensitivity of the materials at failure, associated with leaching. A micromechanical approach for the homogenization of the elastic properties and the strength properties based on the three microstructural levels is developed. These developments allow estimating the relations between the microstructural changes and poroelastic properties including Biot-coefficient and Biot-modulus. In addition, upscaling schemes for the cohesion and friction properties on different levels of cement-based materials are developed.(cont.) Through this the influence of the Interfacial Transition Zone on the strength of intact and leached materials is evaluated. The micromechanical elements of the analysis are combined in a chemoporoplastic constitutive model. The porosity created by calcium dissolution (chemical porosity) is identified as a state variable, relating dissolution process and mechanical properties. The model is implemented in a commercial finite-element program, and model-based simulations show the predictive capability of the developed approach to improve the durability design of concrete structures subjected to calcium leaching.by Franz H. Heukamp.Ph.D

Hippo signaling mediates proliferation, invasiveness, and metastatic potential of clear cell renal cell carcinoma

Recent work has identified dysfunctional Hippo signaling to be involved in maintenance and progression of various human cancers, although data on clear cell renal cell carcinoma (ccRCC) have been limited. Here, we provide evidence implicating aberrant Hippo signaling in ccRCC proliferation, invasiveness, and metastatic potential. Nuclear overexpression of the Hippo target Yes-associated protein (YAP) was found in a subset of patients with ccRCC. Immunostaining was particularly prominent at the tumor margins and highlighted neoplastic cells invading the tumor-adjacent stroma. Short hairpin RNA-mediated knockdown of YAP significantly inhibited proliferation, migration, and anchorage-independent growth of ccRCC cells in soft agar and led to significantly reduced murine xenograft growth. Microarray analysis of YAP knockdown versus mock-transduced ccRCC cells revealed down-regulation of endothelin 1, endothelin 2, cysteine-rich, angiogenic inducer, 61 (CYR61), and c-Myc in ccRCC cells as well as up-regulation of the cell adhesion molecule cadherin 6. Signaling pathway impact analysis revealed activation of the p53 signaling and cell cycle pathways as well as inhibition of mitogen-activated protein kinase signaling on YAP down-regulation. Our data suggest CYR61 and c-Myc as well as signaling through the endothelin axis as bona fide downstream effectors of YAP and establish aberrant Hippo signaling as a potential therapeutic target in ccRCC