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Thomas Greither,1,* Kersten Fischer,2,* Gerit Theil,2 Marios Marcou,1,2 Hans-Juergen Holzhausen,3 Katrin Weigelt,4 Ginette Serrero,5,6 David Hicks,5 Binbin Yue,5 Paolo Fornara,2 Bernd Wullich,4 Helge Taubert,4 Sven Wach,4 Verena Lieb4 1Center for Reproductive Medicine and Andrology, Martin Luther University Halle-Wittenberg, Halle, Germany; 2Department of Urology, Martin Luther University Halle-Wittenberg, Halle, Germany; 3Department of Pathology, Martin Luther University Halle-Wittenberg, Halle, Germany; 4Department of Urology and Pediatric Urology, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; 5A&G Pharmaceutical Inc., Columbia, Maryland, USA; 6Program in Oncology, University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, Maryland, USA *These authors contributed equally to this work Background: GP88/Progranulin is a well-recognized cell growth promoter in different cancers, and elevated serum GP88 levels have been described as negative prognostic factor in breast cancer. However, serum levels in prostate cancer (PCa) patients have not yet been studied. Material and Methods: We analyzed serum GP88 levels by enzyme immunosorbent assay and correlated them with clinicopathological parameters in PCa patients. PCa patients were separated into two groups based on the serum GP88 median level (low ≤44.56 ng/mL or high >44.56 ng/mL) and according to their median age (younger ≤66 years or elder patients >66 years). Results: Low serum GP88 levels were more often detected in younger patients and high levels in elder patients (P=0.018; Fisher’s exact test). PCa patients were separated into three groups, Gleason score (GS) ≤6; GS=7; and GS≥8. In receiver operating characteristic analyses, we could distinguish GS≤6 from GS=7 [area under the curve (AUC): 0.646; P=0.018] and GS≤6 from GS≥8 (AUC: 0.629; P=0.048) but not GS=7 from GS≥8. For survival analysis, GP88 levels were separated into two groups by an optimized cutoff value of 36.92 ng/mL. Using this GP88 stratification, all PCa patients and younger patients with a low serum GP88 level had a significantly better overall survival compared with patients with higher serum GP88 levels (log-rank test P=0.010 and P=0.024). Conclusion: Serum GP88 levels are significantly different depending on age and GS, and they are associated with the prognosis of PCa patients. Keywords: GP88, progranulin, prostate cancer, Gleason score

Post-shot modeling of NIF capsule implosions was performed in order to validate our physical and numerical models. Cryogenic layered target implosions and experiments with surrogate targets produce an abundance of capsule performance data including implosion velocity, remaining ablator mass, times of peak x-ray and neutron emission, core image size, core symmetry, neutron yield, and x-ray spectra. We have attempted to match the integrated data set with capsule-only simulations by adjusting the drive and other physics parameters within expected uncertainties. The simulations include interface roughness, time-dependent symmetry, and a model of mix. We were able to match many of the measured performance parameters for a selection of shots.

Ignition implosions on the National Ignition Facility (NIF) [Lindl et al., Phys. Plasmas 11, 339 (2004)] are driven with a very carefully tailored sequence of four shock waves that must be timed to very high precision in order to keep the fuel on a low adiabat. The first series of precision tuning experiments on NIF have been performed. These experiments use optical diagnostics to directly measure the strength and timing of all four shocks inside the hohlraum-driven, cryogenic deuterium-filled capsule interior. The results of these experiments are presented demonstrating a significant decrease in the fuel adiabat over previously un-tuned implosions. The impact of the improved adiabat on fuel compression is confirmed in related deuterium-tritium (DT) layered capsule implosions by measurement of fuel areal density (ρR), which show the highest fuel compression (ρR ∼ 1.0 g/cm2) measured to date.

ErbB3, a member of the ErbB family of receptor tyrosine kinases, is a potent activator of phosphatidyl inositol-3 kinase (PI3K) and mammalian target of rapamycin (mTOR) signaling, driving tumor cell survival and therapeutic resistance in breast cancers. In luminal breast cancers, ErbB3 upregulation following treatment with the antiestrogen fulvestrant enhances PI3K/mTOR-mediated cell survival. However, the mechanism by which ErbB3 is upregulated in fulvestrant-treated cells is unknown. We found that ErbB3 protein levels and cell surface presentation were increased following fulvestrant treatment, focusing our attention on proteins that regulate ErbB3 at the cell surface, including Nrdp1, NEDD4 and LRIG1. Among these, only LRIG1 correlated positively with ERα, but inversely with ErbB3 in clinical breast cancer data sets. LRIG1, an estrogen-inducible ErbB downregulator, was decreased in a panel of fulvestrant-treated luminal breast cancer cells. Ectopic LRIG1 expression from an estrogen-independent promoter uncoupled LRIG1 from estrogen regulation, thus sustaining LRIG1 and maintaining low ErbB3 levels in fulvestrant-treated cells. An LRIG1 mutant lacking the ErbB3 interaction motif was insufficient to downregulate ErbB3. Importantly, LRIG1 overexpression improved fulvestrant-mediated growth inhibition, whereas cells expressing the LRIG1 mutant were poorly sensitive to fulvestrant, despite effective ERα downregulation. Consistent with these results, LRIG1 expression correlated positively with increased disease-free survival in antiestrogen-treated breast cancer patients. These data suggest that ERα-dependent expression of LRIG1 dampens ErbB3 signaling in luminal breast cancer cells, and by blocking ERα activity with fulvestrant, LRIG1 is decreased thus permitting ErbB3 accumulation, enhanced ErbB3 signaling to cell survival pathways and blunting therapeutic response to fulvestrant.

This study advances understanding of the flow dependency of invertebrate drift in rivers and its relevance to drift-feeding fish. Background drift concentration varied spatially and with flow over natural flow recession (lower mid-range to low flow) in a reach of a New Zealand river, largely consistent with passive entrainment. Seven taxonomic groups (dominated by Leptophlebiidae and Chironomidae) exhibited positive drift concentration-flow relationships, and one (sandy/stony-cased caddisflies (Conoesucidae)) exhibited negative relationships. A mechanistic drift transport model accurately predicted the slope, but not y intercept, of the drift concentration-flow relationship for the total drift community that positively responded to flow but performed more poorly at the taxon or size-class level. Partitioning the relative influence of drift entry and dilution revealed that positive drift concentration-flow relationships arose from entry overwhelming dilution with increasing flow. Drift transport models have potential for predicting relative (%) effects of flow change on concentration and rate of drift-prone invertebrates. This paves the way for drift transport models to inform inputs to net rate of energy intake models for drift-feeding fish. L'etude rehausse la comprehension de l'effet du debit sur la derive d'invertebres dans les rivieres et de son importance pour les poissons s'alimentant d'organismes a la derive. La concentration de fond de la derive varie dans l'espace et en fonction du debit durant la recession naturelle du debit (de debit moyen-faible a faible) dans un troncon d'une riviere neo- zelandaise, concordant generalement avec un entramement passif. Pour sept groupes taxonomiques (domines par les leptophlebiides et les chironomides), les relations entre la concentration de la derive et le debit sont positives, alors que pour un groupe (les trichopteres conoesucides), ces relations sont negatives. Un modele de transport d'organismes a la derive mecaniste predit avec exactitude la pente, mais non l'ordonnee a l'origine de la relation entre la concentration et le debit pour la communaute totale d'organismes a la derive qui reagit positivement au debit, mais il donne de moins bons resultats au niveau du taxon ou de la classe de taille. La separation des influences relatives de l'entree dans la derive et de la dilution revele que les relations positives entre la concentration de la derive et le debit decoulent du fait que, a debits eleves, l'entree dans la derive supplante la dilution. Les modeles de transport a la derive ont le potentiel de predire les effets relatifs (%) de modifications du debit sur la concentration et la vitesse des invertebres susceptibles de deriver. Ainsi, ces modeles pourraient produire des intrants pour des modeles du taux net d'apport d'energie pour les poissons s'alimentant d'organismes a la derive. [Traduit par la Redaction], Introduction As demand for water increases worldwide, water managers are under pressure to prescribe environmental flows that allow for human needs while maintaining riverine processes and ecosystems and associated values. [...]

We use two‐dimensional physics‐based numerical modeling to study multi‐decadal evolution of vegetation and morphology under different flow regimes in real‐world gravel‐bed braided rivers. To assess model realism, we focus on two rivers in Canterbury (New Zealand) that, despite having been subjected to the introduction of similar invasive vegetation species in the last ∼100 years, show very different trajectories of vegetation presence due to their different flow regimes: the Lower Waitaki River and the Waimakariri River. The former, featuring a naturally damped flow regime—and having experienced further artificial flow damping due to hydropower generation from the 1930s, experienced vegetation encroachment; while the latter, featuring a flashy flow regime, retains an unvegetated braided planform. We propose an innovative calibration and validation procedure to determine an optimal setup of vegetation parameters that allows the model to robustly reproduce the trajectories of both rivers, thereby proving that the model responds sensibly to different hydrological conditions. Then, we isolate the impact of hydropower‐related flow regime modifications on vegetation encroachment in the Lower Waitaki by running the calibrated model with a natural flow regime that does not feature the effect of hydropower generation, and find that vegetation encroachment would have happened even without flow alteration, albeit to a milder degree. Finally, we apply to simulation results a conceptual framework based on a synthetic parameter that compares the relative strength of hydrological and vegetation controls, and discuss the use of this parameter as a predictor of vegetation presence across flow regimes. Plain Language Summary: We study how numerical models can predict the amount of vegetation that establishes on the gravelly bed of wide rivers. We focus on two rivers in New Zealand: the Waimakariri River, having frequent and intense floods, and the Lower Waitaki River, with less frequent and intense floods. This milder character of the Waitaki relates to the presence in the river catchment of three natural lakes that store flood flows and release them slowly, and to the additional storage of artificial hydropower reservoirs. Both rivers have been exposed to invasive vegetation that tends to spread on their beds; however, vegetation spread was significantly more pronounced in the Waitaki than in the Waimakariri. First, we find the parameter values that allow the model to reproduce the vegetation changes seen in both rivers. Then, we simulate the vegetation changes that would have happened in the Waitaki had the hydropower reservoirs not been built, finding there would still have been significant vegetation spread. Finally, we interpret the intensity of vegetation spread as depending on the frequency of floods and on the speed of vegetation growth: a higher vegetation presence is found if vegetation grows faster and if the floods are more spaced in time. Key Points: Calibration and validation on two rivers with same vegetation species but different hydrology ensures model's sensible response and realismNumerical modeling allows quantification of the impact of a hydropower scheme on vegetation encroachment in a braided riverThe ratio between inter‐flood period duration and vegetation growth timescale is a key control and predictor of vegetation presence [ABSTRACT FROM AUTHOR]