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In Plantago lanceolata L. the effect of Cu(II) additions to the nutrient solution on root-associated Fe(III) reductase was studied in a factorial design with different Cu(II) and Fe(III) concentrations. Iron starvation resulted in approx. an eightfold increase in root Fe reduction at the level of intact plants and twofold enhancement in the specific activity of both NADH-linked FeEDTA reductase and H+-ATPase in isolated root plasma membrane vesicles. In plants exposed to low (0.3-0.7 μM) Cu and suboptimal Fe levels, reduction activity at the root surface was further increased and associated with more severe interveinal chlorosis than plants grown in Cu- free medium. In Fe-sufficient plants, withholding Cu over a prolonged period slightly enhanced the reduction activity. Addition of high (5 μM) Cu concentrations to Fe-free medium inhibited the induction of the physiological responses by Fe-deficiency stress. In plants without Fe supply but with adequate Cu supply, short-term application of 5 μM CuSO4 completely inhibited the reduction activity. Neither incubation of the plasma membrane vesicles before measurement nor incubation of intact plants with Cu before isolation caused a significant decrease in reductase activity. The results are interpreted as indicating different mechanisms underlying Cu-induced alterations in iron nutrition. [ABSTRACT FROM AUTHOR]

Background: Sarcomatoid differentiation/histology of renal cell carcinoma (sRCC) in patients with metastatic renal cell carcinoma (mRCC) is still underresearched in current therapy regimes. We aimed to evaluate the impact of sRCC on outcomes in patients with mRCC treated with tyrosine kinase inhibitors (TKIs). Methods: We collected complete data of 262 consecutive mRCC patients from our institutional database for this retrospective study. All patients were treated with TKIs within a single or multimodal treatment approach. All analyses were adjusted for the presence of sRCC. Descriptive statistics as well as uni- and multivariable outcome metrics, including progression-free (PFS) and overall survival (OS) as endpoints were performed. Results: Overall, 18 patients had sRCC (6.9%). Patients with sRCC had more often clear-cell histology ( p = 0.047), a higher T-stage ( p = 0.048), and underwent cytoreductive nephrectomy more frequently ( p < 0.001). The most common first-line TKIs were Sunitinib (65.6%), Sorafenib (19.5%), and Pazopanib (10.3%), respectively. At a median follow-up of 32 months, patients with sRCC had significantly reduced PFS ( p = 0.02) and OS ( p = 0.01) compared to patients without sRCC. In multivariable analyses that adjusted for the effects of standard mRCC predictors, the sarcomatoid feature retained its independent association with inferior PFS (HR: 2.39; p = 0.007) and OS (HR: 2.37; p = 0.001). This association remained statistically significant in subgroup analyses of patients with Sunitinib as first-line therapy (PFS p < 0.001; OS: p < 0.001). Conclusion: Despite its rare occurrence, our findings confirm sRCC as a powerful predictor for inferior outcomes in mRCC treated with targeted therapies. This suggests a need for more tailored treatment strategies in patients harboring mRCC with sarcomatoid histology to improve oncological outcomes., Competing Interests: SFS is consulting or advising the following: Astra Zeneca, BMS, Ferring, Ipsen, Jansen, MSD, Olympus, Pfizer, Pierre Fabre, Richard Wolf, Roche, Sanochemia, and Urogen. MR is a speaker for Bayer Healthcare, Bristol Myer Squibb, EUSA Pharma, IPSEN Pharma, Novartis, Roche, and Pfizer. MR is a consultant and/or received honoraria by Bayer Healthcare, Bristol Myer Squibb, IPSEN Pharma, MSD, Novartis, Roche, and Pfizer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a shared affiliation with one of the authors, SFS, at the time of review., (Copyright © 2021 Janisch, Kienapfel, Fühner, Klotzbücher, Marks, Hillemacher, Meyer, Iwata, Parizi, Sauter, Fisch, Shariat, Dahlem and Rink.)

Background: Predictive markers can help tailor treatment to the individual in metastatic renal cell carcinoma (mRCC). De Ritis ratio (DRR) is associated with oncologic outcomes in various solid tumors., Objective: To assess the value of DRR in prognosticating survival in mRCC patients treated with tyrosine-kinase inhibitors (TKI)., Methods: Overall, 220 mRCC patients treated with TKI first-line therapy were analyzed. An optimal cut-off point for DRR was determined with Youden's J. We used multiple strata for DRR, performed descriptive, Kaplan-Meier and multivariable Cox-regression analyses to assess associations of DRR with progression-free (PFS) and overall survival (OS)., Results: Patients above the optimal cut-off point for DRR of ≥ 1.58 had fewer liver metastases (p = 0.01). There was no difference in PFS (p > 0.05) between DRR groups. DRR above the median of 1.08 (HR 1.42; p = 0.03), DRR ≥ 1.1(HR 1.44; p = 0.02), ≥ 1.8 (HR 1.56; p = 0.03), ≥ 1.9 (HR 1.59; p = 0.02) and ≥ 2.0 (HR 1.63; p = 0.047) were associated with worse OS. These associations did not remain after multivariable adjustment. In the intermediate MSKCC group, DRR was associated with inferior OS at cut-offs ≥ 1.0 (HR 1.78; p = 0.02), ≥ 1.1 (HR 1.81; p = 0.01) and above median (HR 1.88; p = 0.007) in multivariable analyses. In patients with clear-cell histology, DRR above median (HR 1.54; p = 0.029) and DRR ≥ 1.1 (HR 1.53; p = 0.029) were associated with OS in multivariable analyses., Conclusion: There was no independent association between DRR and survival of mRCC patients treated with TKI in the entire cohort. However, OS of patients with intermediate risk and clear-cell histology were affected by DRR. DRR could be used for tailored decision-making in these subgroups., (© 2021. The Author(s).)