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Resistance to therapies targeting the epidermal growth factor receptor (EGFR), such as cetuximab, remains a major roadblock in the search for effective therapeutic strategies in head and neck squamous cell carcinoma (HNSCC). Due to its close interaction with the EGFR pathway, redundant or compensatory activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway has been proposed as a major driver of resistance to EGFR inhibitors. Understanding the role of each of the main proteins involved in this pathway is utterly important to develop rational combination strategies able to circumvent resistance. Therefore, the current work reviewed the role of PI3K/Akt pathway proteins, including Ras, PI3K, tumor suppressor phosphatase and tensing homolog, Akt and mammalian target of rapamycin in resistance to anti-EGFR treatment in HNSCC. In addition, we summarize PI3K/Akt pathway inhibitors that are currently under (pre)clinical investigation with focus on overcoming resistance to EGFR inhibitors. In conclusion, genomic alterations in and/or overexpression of one or more of these proteins are common in both human papillomavirus (HPV)-positive and HPV-negative HNSCC tumors. Therefore, downstream effectors of the PI3K/Akt pathway serve as promising drug targets in the search for novel therapeutic strategies that are able to overcome resistance to anti-EGFR treatment. Co-targeting EGFR and the PI3K/Akt pathway can lead to synergistic drug interactions, possibly restoring sensitivity to EGFR inhibitors and hereby improving clinical efficacy. Better understanding of the predictive value of PI3K/Akt pathway alterations is needed to allow the identification of patient populations that might benefit most from these combination strategies.

To optimize the dosing regimen in patients with severe renal impairment based on population pharmacokinetic (PPK)/pharmacodynamic analysis.

The pharmacokinetics and safety of nemonoxacin was evaluated in a single-dose, open-label, nonrandomized, parallel-group study after single oral dose of a 0.5-g nemonoxacin capsule in 10 patients with severe renal impairment and 10 healthy controls. Both blood and urine samples were collected within 72 hours after admission and determined the concentrations. A PPK model was built using nonlinear mixed effects modelling. The probability of target attainment and the cumulative fraction of response against Streptococcus pneumoniae and Staphylococcus aureus was calculated by Monte Carlo simulation.

The data best fitted a 2-compartment model, from which the PPK parameters were estimated, including clearance (8.55 L/h), central compartment volume (80.8 L) and peripheral compartment volume (50.6 L). The accumulative urinary excretion was 23.4 ± 6.5% in severe renal impairment patients and 66.1 ± 16.8% in healthy controls. PPK/pharmacodynamic modelling and simulation of 4 dosage regimens found that nemonoxacin 0.5 g every 48 hours (q48h) was the optimal dosing regimen in severe renal impairment patients, evidenced by higher probability of target attainment (92.7%) and cumulative fraction of response (>99%) at nemonoxacin minimum inhibitory concentration ≤ 1 mg/L against S. pneumoniae and S. aureus. The alternative regimens (0.25 g q24h; loading dose 0.5 g on Day 1 followed by 0.25 g q24h) were insufficient to cover the pathogens even if minimum inhibitory concentration = 1 mg/L.

An extended dosing interval (0.5 g q48h) may be appropriate for optimal efficacy of nemonoxacin in case of severe renal impairment.

An extended dosing interval (0.5 g q48h) may be appropriate for optimal efficacy of nemonoxacin in case of severe renal impairment.Replicability of results is regarded as the corner stone of science. Recent research seems to raise doubts about whether this requirement is generally fulfilled. Often, replicability of results is defined as repeating a statistically significant result. However, since significance may not imply scientific relevance, dual-criterion study designs that take both aspects into account have been proposed and investigated during the last decade. Originally developed for proof-of-concept trials, the design could be appropriate for phase III trials as well. In fact, a dual-criterion design has been requested for COVID-19 vaccine applications by major health authorities. In this article, replicability of dual-criterion designs is investigated. It turns out that the probability to replicate a significant and relevant result can become as low as 0.5. The replication probability increases if the effect estimator exceeds the minimum relevant effect in the original study by an extra amount.The tailings spilled by the Fundão Dam rupture in the Doce River basin (Brazil) had a high pH, elevated sodium (Na) and ether amine, and low soil organic matter. With the aim of decreasing the toxic compounds, we established 2 remediation strategies treatment 1, phytoremediation with tolerant native species of the Atlantic Forest cultivated on scraped sediment plus the incorporation of organic matter; and treatment 2, phytoremediation with native species plus superficial deposition of organic matter. The experimental site was compared with a degraded site that the dam tailings had reached and with a preserved site, a fragment of preserved Atlantic Forest. After 12 mo, plants showed an outstanding growth, especially after treatment 1 (~4 m), and the remediation procedures resulted in significant decreases in pH (from 8.0 to ~6.0), Na (from 154 to 22-35 mg/kg), electrical conductivity, and ether amine (from 6.0 to 0.5 mg/kg) in both treatments. By contrast, ammonium, a product of ether amine degradation, showed a significant increase in the experimental site, along with a significant increase in nitrate and improvement of soil microbial populations assessed by phospholipid fatty acid analysis. The treatments also improved soil fertility in the experimental site, as estimated by soil nutrients, cation exchange capacity, and soil aggregation. Based on the parameters analyzed, a principal component analysis showed that samples from the degraded site and the preserved site clustered in an opposite position and those from the experimental site clustered in an intermediate position but closer to the samples from the preserved site. Overall, our results demonstrated that the remediation procedures adopted were effective and resulted in the rehabilitation of a riparian forest over dam tailings contaminated with Na and ether amine. Environ Toxicol Chem 2021;001-15. Akt inhibitor © 2021 SETAC.