A Phase I Study of the Oral Dual-Acting Pan-PI3K/mTOR Inhibitor Bimiralisib in Patients with Advanced Solid Tumors.

BACKGROUND: Bimiralisib is a pan-PI3K/mTOR inhibitor demonstrating antitumor efficacy in preclinical models. The objectives of this study were to identify a maximum tolerated dose (MTD), pharmacokinetics (PK), a dosing schedule, and adverse events (AEs) in patients with advanced solid tumors. PATIENTS AND METHODS: Patients received oral bimiralisib to determine the MTD of one continuous (once daily) and two intermittent schedules (A: Days 1, 2 weekly; B: Days 1, 4 weekly) until progression or unacceptable AEs occurred. RESULTS: The MTD for the continuous schedule was 80 mg, with grade three fatigue as the dose-limiting toxicity (DLT). No MTD was reached with intermittent schedules, with only one DLT in schedule B. PK analysis suggested that 140 mg (schedule A) was within the biologically active dose range and was selected for further exploration. The most frequent treatment-emergent AEs were hyperglycemia (76.2%) in the continuous schedule, and nausea (56-62.5%) in schedules A and B. The most frequent treatment-emergent > grade three AE for all schedules combined was hyperglycemia (28.6%, continuous schedule; 12.0%, schedule A; 12.5%, schedule B). There was one partial response in a head and neck squamous cancer patient with a NOTCH1T1997M mutation. CONCLUSIONS: Bimiralisib demonstrated a manageable AE profile consistent with this compound class. Intermittent schedules had fewer > grade three AEs, while also maintaining favorable PK profiles. Intermittent schedule A is proposed for further development in biomarker-selected patient populations.

[Perceived changes in the workload of home care nurses during the COVID-19 pandemic: Results of an online survey]. / Wahrgenommene Veränderungen der Belastungssituation ambulant Pflegender während der COVID-19-Pandemie: Ergebnisse einer Online-Befragung.

BACKGROUND: The COVID-19 pandemic posed major challenges to the health care system, particularly to nursing. Intensive care was often the focus of attention. However, home care nursing was also confronted with drastic changes, while it is largely unknown how the work situation changed for employees as a result of the pandemic - also depending on the sponsorship of home care nursing services. METHODS: A nationwide online survey of home-care nurses was conducted in May and June 2022. The Intensification of Job Demands Scale (IDS) and an open question regarding changes in the work situation due to the pandemic were used among other instruments. RESULTS: More than two-thirds of the 976 home-care nurses surveyed agreed with the respective statements regarding work intensification (e.g., taking fewer breaks, doing work activities at the same time, not having enough time). Additional factors for psychological workload during the pandemic primarily fell within the scope of work organization (e.g., staff absences due to illness and quarantine, vaccination related leaves and terminations, additional workload due to handling protective clothing). Employees of privately run care services experienced fewer COVID-19-related changes than home care nurses employed by non-profit providers. CONCLUSION: In future crisis situations, good information management (e.g., uniform, consistent and comprehensible guidelines and recommendations for action) and ways to compensate for staff shortages should be created.

Control of Yu-Shiba-Rusinov States through a Bosonic Mode.

We investigate the impact of a bosonic degree of freedom on Yu-Shiba-Rusinov states emerging from a magnetic impurity in a conventional superconductor. Starting from the Anderson impurity model, we predict that an additional p-wave conduction band channel opens up if a bosonic mode is coupled to the tunneling between impurity and host, which implies an additional pair of odd-parity Yu-Shiba-Rusinov states. The bosonic mode can be a vibrational mode or the electromagnetic field in a cavity. The exchange couplings in the two channels depend sensitively on the state of the bosonic mode (ground state, few quanta, or classically driven Floquet state), which opens possibilities for phononics or photonics control of such systems, with a rich variety of ground and excited states.

Osmotic shrinkage elicits FAK- and Src phosphorylation and Src-dependent NKCC1 activation in NIH3T3 cells.

The mechanisms linking cell volume sensing to volume regulation in mammalian cells remain incompletely understood. Here, we test the hypothesis that activation of nonreceptor tyrosine kinases Src, focal adhesion kinase (FAK), and Janus kinase-2 (Jak2) occurs after osmotic shrinkage of NIH3T3 fibroblasts and contributes to volume regulation by activation of NKCC1. FAK phosphorylation at Tyr397, Tyr576/577, and Tyr861 was increased rapidly after exposure to hypertonic (575 mOsm) saline, peaking after 10 (Tyr397, Tyr576/577) and 10-30 min (Tyr861). Shrinkage-induced Src family kinase autophosphorylation (pTyr416-Src) was induced after 2-10 min, and immunoprecipitation indicated that this reflected phosphorylation of Src itself, rather than Fyn and Yes. Phosphorylated Src and FAK partly colocalized with vinculin, a focal adhesion marker, after hypertonic shrinkage. The Src inhibitor pyrazolopyrimidine-2 (PP2, 10 µM) essentially abolished shrinkage-induced FAK phosphorylation at Tyr576/577 and Tyr861, yet not at Tyr397, and inhibited shrinkage-induced NKCC1 activity by ∼50%. The FAK inhibitor PF-573,228 augmented shrinkage-induced Src phosphorylation, and inhibited shrinkage-induced NKCC1 activity by ∼15%. The apparent role of Src in NKCC1 activation did not reflect phosphorylation of myosin light chain kinase (MLC), which was unaffected by shrinkage and by PP2, but may involve Jak2, a known target of Src, which was rapidly activated by osmotic shrinkage and inhibited by PP2. Collectively, our findings suggest a major role for Src and possibly the Jak2 axis in shrinkage-activation of NKCC1 in NIH3T3 cells, whereas no evidence was found for major roles for FAK and MLC in this process.

Learning, specialization, efficiency and task allocation in social insects.

One of the most spectacular features of social insect colonies is their division of labor. Although individuals are often totipotent in terms of the labor they might perform, they might persistently work as scouts, fighters, nurses, foragers, undertakers or cleaners with a repetitiveness that might resemble an assembly line worker in a factory. Perhaps because of this apparent analogy, researchers have often assumed a priori that such labor division must be efficient, but empirical proof is scarce. New work on Themnothorax ants shows that there might be no link between an individual's propensity to perform a task, and their efficiency at that task, nor are task specialists more efficient than generalists. Here we argue that learning psychology might provide the missing link between social insect task specialization and efficiency: just like in human societies, efficiency at a job specialty is only partially a result of "talent", or innate tendency to engage in a job: it is much more a result of perfecting skills with experience, and the extent to which experience can be carried over from one task to the next (transfer), or whether experience at one task might actually impair performance at another (interference). Indeed there is extensive circumstantial evidence that learning is involved in almost any task performed by social insect workers, including food type recognition and handling techniques, but also such seemingly basic tasks as nest building and climate control. New findings on Cerapachys ants indicate that early experience of success at a task might to some extent determine the "profession" an insect worker chooses in later life.

Animal personalities: the advantage of diversity.

Animals do not always perform to the best of their abilities when faced with difficult choices. New findings on foraging honeybees show that co-existing strategies, where some individuals place more emphasis on accuracy and others on speed, can be advantageous to the colony in a variable environment.