Clinical impact of MDR1-expression in testicular germ cell cancer

Aim: The multidrug resistance protein 1 (MDR1, P-gp, p-170) is a membrane glycoprotein that acts as an energy-dependent drug efflux pump. In various malignancies its expression is associated with resistance to diverse cytostatic drugs, and therefore predicts resistance to systemic treatment. The aim of this study was to investigate the prognostic value of MDR1 expression in primary tumor tissue to predict necrosis or viable cancer in residual tumor masses after systemic chemotherapy for advanced testicular germ cell cancer. Materials and Methods: Out of 77 patients, histopathological characteristics of primary testicular cancer specimens and retroperitoneal lymph node dissection (RPLND) samples following chemotherapy were available from 72 and all 77 patients, respectively. Moreover, MDR1 expression was determined by immunohistochemistry in 47 primary tumors and corresponding 73 RPLND sections. Results: After chemotherapy and subsequent RPLND, the examination of residual tumor masses revealed that mature teratoma and active viable tumor were predominantly found in patients with non-seminoma (NSGCT; p = 0.048), especially in those with containing mature teratoma (p = 0.001). Moreover, using univariate analysis the expression of MDR1 in the primary testicular tumor predicted viable tumor/teratoma residues in RPLND sections (p = 0.003). However, in multivariate analysis including the tumors’ histological subtype, MDR1 expression alone failed to reach statistical significance as an independent prognostic marker for residual vital tumor (p ≥ 0.16). Conclusions: With the limited number of patients given, the correlation between MDR1 expression in primary testis cancer and active residual retroperitoneal disease after chemotherapy failed to reach statistical significance as in independent marker. Therefore, up to now routine MDR1 staining of testicular germ cell cancer samples should not be performed in clinical practice. However, as there was a clear trend, a larger number of patients suffering from metastatic non-seminomas should be studied, as MDR1 expression might have significant prognostic value in this particular subgroup of patients.Белок 1 множественной лекарств енной устойчив ости (MDR1, P-gp, p-170) – это мембранный гликопротеин, функционирующий как энергозависимый насос. При разл ичных фо рмах опухолей его экспр е ссия связана с устойчив о стью опухоли к различным цитостатикам, что может быть использовано для выбора типа терапии. Цель работы — исследование прогности- ческой значимости экспрессии MDR1 в ткани пе рвичной опухоли для оценки возмо жности раз вития некроза или сохран е ния живых клеток в остаточной ткани опухоли после применения системной химиотерапии на поздних стадиях герминативных опухолей яичка. Материалы и методы: про анализиро ваны гисто патоло гические характ е ристики пе рвично й те стикулярной опухоли и образцов, полученных при иссечении ретроперитонеальных лимфатических узлов (RPLND) после хими отерапии 72 и 77 бол ьных соотве тственно. Экспр ессию MDR1 определяли иммун огист охимич еским методом в 47 образцах первичн ой опухоли и соответствующих 73 ср RPLND. Результаты: после хими отерапии и последующей RPLNDисследовани е оста- точных опухолевых тканей показало, чтозрелая тератома и жизнеспособные опух олевые клетки выяв ляют преимущественно у больных, у которых не была обнаружена семинома (NSGCT; p = 0,048), особенно у так овых , у которых была тератома (p = 0,001). Более того, д анные одно факторного анализа показали, что экспр е ссия MDR1 в ткани пе рвично й те стику лярной опу- холи может служить прогностич еским факт ором сохран ения живых опух олевых клеток срезах RPLND (p = 0,003). О нак о применение мультифакторного анализа, в том числе с учетом гистологического подтипа опухоли, показало, что экспр е ссия MDR1 не имеет самостоятельной прогностической значимости для выявления живых остаточных опух олевых клеток (p 0,16). Выводы: ввиду небольшо йвыборкибольных не выяв лено статистически значимойкорреляции между экспр ессией MDR1 в первичной опухоли яичка и наличием активных резидуальных очагов поражения в ретроперитонеальном пространстве. В т о же время, учитывая выявленную тенденцию, экспрессию MDR1, в качестве возможного прогностич еского марк ера, имеет смысл исследовать именно у больных с метастатическими опухолями, не являющимися семиномой

Mixed-Morphology Supernova Remnants in X-rays: Isothermal Plasma in HB21 and Probable Oxygen-Rich Ejecta in CTB 1

(Abridged) We present an analysis of X-ray observations made of the Galactic supernova remnants (SNRs) HB21 (G89.0+4.7) and CTB 1 (G116.9+0.2), two well-known mixed-morphology (MM) SNRs. We find a marked contrast between the X-ray properties of these SNRs: for HB21, the extracted ASCA spectra of the northwest and southeast regions of the X-ray emitting plasma can be fit with a single thermal model with marginally enhanced silicon and sulfur abundances. For both of these regions, the derived column density and temperature are N_H~0.3x10^22 cm^-2 and kT~0.7 keV, respectively. No significant spatial differences in temperature or elemental abundances between the two regions are detected and the X-ray-emitting plasma in both regions is close to ionization equilibrium. Our Chandra spectral analysis of CTB 1 reveals that this source is likely an oxygen-rich SNR with enhanced abundances of oxygen and neon. The extracted ASCA spectra for the southwestern and northeastern regions of CTB 1 cannot be fit with a single thermal component. Based on our fits to these spectra, we derive a column density N_H~0.6x10^22 cm^-2 and a temperature for the soft thermal component of kT_soft~0.28 keV. The hard emission from the southwest may be modeled with either a thermal component (kT_hard~3 keV) or by a power law component (Gamma~2-3) while the hard emission from the northeast may be modeled with a power law component (Gamma~1.4). We have also extracted ASCA GIS spectra of the discrete X-ray source 1WGA J0001.4+6229 which is seen in projection toward CTB 1. These spectra are best fit using a power-law model with a photon index Gamma=2.2^{+0.5}_{-1.2} which is typical for featureless power-law continua produced by rotation-powered pulsars. This source may be a neutron star associated with CTB 1.Comment: 46 pages, 16 figures, accepted for publication in the Astronomical Journa

Six Years of Chandra Observations of Supernova Remnants

We present a review of the first six years of Chandra X-ray Observatory observations of supernova remnants. From the official "first-light" observation of Cassiopeia A that revealed for the first time the compact remnant of the explosion, to the recent million-second spectrally-resolved observation that revealed new details of the stellar composition and dynamics of the original explosion, Chandra observations have provided new insights into the supernova phenomenon. We present an admittedly biased overview of six years of these observations, highlighting new discoveries made possible by Chandra's unique capabilities.Comment: 82 pages, 28 figures, for the book Astrophysics Update

A Sino-German λ\lambda6\ cm polarization survey of the Galactic plane. V. Large supernova remnants

Observations of large supernova remnants (SNRs) at high frequencies are rare, but provide valuable information about their physical properties. The total intensity and polarization properties of 16 large SNRs in the Galactic plane were investigated based on observations of the Urumqi $\lambda$6\ cm polarization survey of the Galactic plane with an angular resolution of 9\farcm5. We extracted total intensity and linear polarization maps of large SNRs from the Urumqi $\lambda$6\ cm survey, obtained their integrated flux densities, and derived the radio spectra in context with previously published flux densities at various frequencies. In particular, Effelsberg $\lambda$11\ cm and $\lambda$21\ cm survey data were used for calculating integrated flux densities. The $\lambda$6\ cm polarization data also delineate the magnetic field structures of the SNRs. We present the first total intensity maps at $\lambda$6\ cm for SNRs G106.3+2.7, G114.3+0.3, G116.5+1.1, G166.0+4.3 (VRO 42.05.01), G205.5+0.5 (Monoceros Nebula) and G206.9+2.3 (PKS 0646+06) and the first polarization measurements at $\lambda$6\ cm for SNRs G82.2+5.3 (W63), G106.3+2.7, G114.3+0.3, G116.5+1.1, G166.0+4.3 (VRO 42.05.01), G205.5+0.5 (Monoceros Nebula) and G206.9+2.3 (PKS 0646+06). Most of the newly derived integrated radio spectra are consistent with previous results. The new flux densities obtained from the Urumqi $\lambda$6\ cm, Effelsberg $\lambda$11\ cm and $\lambda$21\ cm surveys are crucial to determine the spectra of SNR G65.1+0.6, G69.0+2.7 (CTB 80), G93.7-0.2 and G114.3+0.3. We find that G192.8$-$1.1 (PKS 0607+17) consists of background sources, \ion{H}{II} regions and the extended diffuse emission of thermal nature, and conclude that G192.8$-$1.1 is not a SNR.Comment: 15 pages, 10 figures, accepted by A&\amp;A. Language improved. For the version with high resolution figures, please go to: http://zmtt.bao.ac.cn/6cm/paper/gxy_largeSNR.pd

Milagro Observations of Multi-TeV Emission from Galactic Sources in the Fermi Bright Source List

We present the result of a search of the Milagro sky map for spatial correlations with sources from a subset of the recent Fermi Bright Source List (BSL). The BSL consists of the 205 most significant sources detected above 100 MeV by the Fermi Large Area Telescope. We select sources based on their categorization in the BSL, taking all confirmed or possible Galactic sources in the field of view of Milagro. Of the 34 Fermi sources selected, 14 are observed by Milagro at a significance of 3 standard deviations or more. We conduct this search with a new analysis which employs newly-optimized gamma-hadron separation and utilizes the full 8-year Milagro dataset. Milagro is sensitive to gamma rays with energy from 1 to 100 TeV with a peak sensitivity from 10-50 TeV depending on the source spectrum and declination. These results extend the observation of these sources far above the Fermi energy band. With the new analysis and additional data, multi-TeV emission is definitively observed associated with the Fermi pulsar, J2229.0+6114, in the Boomerang Pulsar Wind Nebula (PWN). Furthermore, an extended region of multi-TeV emission is associated with the Fermi pulsar, J0634.0+1745, the Geminga pulsar.Comment: Accepted for publication in Astrophysical Journal Letters June 30, 200

Taxation in the digital economy - recent policy developments and the question of value creation

The paper reviews the evidence on the challenges of digitalization for direct (corporate profit) and indirect (consumption) taxation. Based on both anecdotal and empirical evidence, we evaluate ongoing developments at the OECD and European Union level and argue that there is no justification for introducing a new tax order for digital businesses. In particular, the significant digital presence and the digital services tax as put forward by the European Commission will most likely distort corporate decisions and spur tax competition. To contribute to the development of tax rules in line with value creation as the gold standard for profit taxation the paper discusses data as a "new" value-driving asset in the digital economy. It draws on insights from interdisciplinary research to highlight that the value of data emerges through proprietary activities conducted within businesses. We ultimately discuss how existing transfer pricing solutions can be adapted to business models employing data mining

In search of disorders: internalizing symptom networks in a large clinical sample.

Background The co‐occurrence of internalizing disorders is a common form of psychiatric comorbidity, raising questions about the boundaries between these diagnostic categories. We employ network psychometrics in order to: (a) determine whether internalizing symptoms cluster in a manner reflecting DSM diagnostic criteria, (b) gauge how distinct these diagnostic clusters are and (c) examine whether this network structure changes from childhood to early and then late adolescence. Method Symptom‐level data were obtained for service users in publicly funded mental health services in England between 2011 and 2015 (N = 37,162). A symptom network (i.e. Gaussian graphical model) was estimated, and a community detection algorithm was used to explore the clustering of symptoms. Results The estimated network was densely connected and characterized by a multitude of weak associations between symptoms. Six communities of symptoms were identified; however, they were weakly demarcated. Two of these communities corresponded to social phobia and panic disorder, and four did not clearly correspond with DSM diagnostic categories. The network structure was largely consistent by sex and across three age groups (8–11, 12–14 and 15–18 years). Symptom connectivity in the two older age groups was significantly greater compared to the youngest group and there were differences in centrality across the age groups, highlighting the age‐specific relevance of certain symptoms. Conclusions These findings clearly demonstrate the interconnected nature of internalizing symptoms, challenging the view that such pathology takes the form of distinct disorders

Observation of Extended VHE Emission from the Supernova Remnant IC 443 with VERITAS

We present evidence that the very-high-energy (VHE, E > 100 GeV) gamma-ray emission coincident with the supernova remnant IC 443 is extended. IC 443 contains one of the best-studied sites of supernova remnant/molecular cloud interaction and the pulsar wind nebula CXOU J061705.3+222127, both of which are important targets for VHE observations. VERITAS observed IC 443 for 37.9 hours during 2007 and detected emission above 300 GeV with an excess of 247 events, resulting in a significance of 8.3 standard deviations (sigma) before trials and 7.5 sigma after trials in a point-source search. The emission is centered at 06 16 51 +22 30 11 (J2000) +- 0.03_stat +- 0.08_sys degrees, with an intrinsic extension of 0.16 +- 0.03_stat +- 0.04_sys degrees. The VHE spectrum is well fit by a power law (dN/dE = N_0 * (E/TeV)^-Gamma) with a photon index of 2.99 +- 0.38_stat +- 0.3_sys and an integral flux above 300 GeV of (4.63 +- 0.90_stat +- 0.93_sys) * 10^-12 cm^-2 s^-1. These results are discussed in the context of existing models for gamma-ray production in IC 443.Comment: 7 pages, accepted by ApJ