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

The Physics of Ultraperipheral Collisions at the LHC

We discuss the physics of large impact parameter interactions at the LHC: ultraperipheral collisions (UPCs). The dominant processes in UPCs are photon-nucleon (nucleus) interactions. The current LHC detector configurations can explore small $x$ hard phenomena with nuclei and nucleons at photon-nucleon center-of-mass energies above 1 TeV, extending the $x$ range of HERA by a factor of ten. In particular, it will be possible to probe diffractive and inclusive parton densities in nuclei using several processes. The interaction of small dipoles with protons and nuclei can be investigated in elastic and quasi-elastic $J/\psi$ and $\Upsilon$ production as well as in high $t$ $\rho^0$ production accompanied by a rapidity gap. Several of these phenomena provide clean signatures of the onset of the new high gluon density QCD regime. The LHC is in the kinematic range where nonlinear effects are several times larger than at HERA. Two-photon processes in UPCs are also studied. In addition, while UPCs play a role in limiting the maximum beam luminosity, they can also be used a luminosity monitor by measuring mutual electromagnetic dissociation of the beam nuclei. We also review similar studies at HERA and RHIC as well as describe the potential use of the LHC detectors for UPC measurements.Comment: 229 Pages, 121 figure

Variation in developmental rates is not linked to environmental unpredictability in annual killifishes

Comparative evidence suggests that adaptive plasticity may evolve as a response to predictable environmental variation. However, less attention has been placed on unpredictable environmental variation, which is considered to affect evolutionary trajectories by increasing phenotypic variation (or bet hedging). Here, we examine the occurrence of bet hedging in egg developmental rates in seven species of annual killifish that originate from a gradient of variation in precipitation rates, under three treatment incubation temperatures (21, 23, and 25 degrees C). In the wild, these species survive regular and seasonal habitat desiccation, as dormant eggs buried in the soil. At the onset of the rainy season, embryos must be sufficiently developed in order to hatch and complete their life cycle. We found substantial differences among species in both the mean and variation of egg development rates, as well as species-specific plastic responses to incubation temperature. Yet, there was no clear relationship between variation in egg development time and variation in precipitation rate (environmental predictability). The exact cause of these differences therefore remains enigmatic, possibly depending on differences in other natural environmental conditions in addition to precipitation predictability. Hence, if species-specific variances are adaptive, the relationship between development and variation in precipitation is complex and does not diverge in accordance with simple linear relationships

A variational approach to the stochastic aspects of cellular signal transduction

Cellular signaling networks have evolved to cope with intrinsic fluctuations, coming from the small numbers of constituents, and the environmental noise. Stochastic chemical kinetics equations govern the way biochemical networks process noisy signals. The essential difficulty associated with the master equation approach to solving the stochastic chemical kinetics problem is the enormous number of ordinary differential equations involved. In this work, we show how to achieve tremendous reduction in the dimensionality of specific reaction cascade dynamics by solving variationally an equivalent quantum field theoretic formulation of stochastic chemical kinetics. The present formulation avoids cumbersome commutator computations in the derivation of evolution equations, making more transparent the physical significance of the variational method. We propose novel time-dependent basis functions which work well over a wide range of rate parameters. We apply the new basis functions to describe stochastic signaling in several enzymatic cascades and compare the results so obtained with those from alternative solution techniques. The variational ansatz gives probability distributions that agree well with the exact ones, even when fluctuations are large and discreteness and nonlinearity are important. A numerical implementation of our technique is many orders of magnitude more efficient computationally compared with the traditional Monte Carlo simulation algorithms or the Langevin simulations.Comment: 15 pages, 11 figure

Transformation of normal human cells in the absence of telomerase activation

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Nodding syndrome in Tanzania may not be associated with circulating anti-NMDA- and anti-VGKC receptor antibodies or decreased pyridoxal phosphate serum levels-a pilot study

Background: Nodding syndrome (NS) is a seemingly progressive epilepsy disorder of unknown underlying cause. We investigated association of pyridoxal-phosphate serum levels and occurrence of anti-neuronal antibodies against N-methyl-D-aspartate (NMDA) receptor and voltage gated potassium channel (VGKC) complex in NS patients.Methods: Sera of a Tanzanian cohort of epilepsy and NS patients and community controls were tested for the presence of anti-NMDA-receptor and anti-VGKC complex antibodies by indirect immunofluorescence assay. Furthermore pyridoxal-phosphate levels were measured.Results: Auto-antibodies against NMDA receptor or VGKC (LG1 or Caspr2) complex were not detected in sera of patients suffering from NS (n=6), NS plus other seizure types (n=16), primary generalized epilepsy (n=1) and community controls without epilepsy (n=7). Median Pyridoxal-phosphate levels in patients with NS compared to patients with primary generalized seizures and community controls were not significantly different. However, these median pyridoxal-phosphate levels are significantly lower compared to the range considered normal in Europeans.Conclusions: In this pilot study NS was not associated with serum anti-NMDA receptor or anti-VGKC complex antibodies and no association to pyridoxal-phosphate serum levels was found.Key words: nodding syndrome, epilepsy, anti-neuronal antibodies, pyridoxal-phosphat