Quantitative systems pharmacology modeling of HER2-positive metastatic breast cancer for translational efficacy evaluation and combination assessment across therapeutic modalities.

HER2-positive (HER2+) metastatic breast cancer (mBC) is highly aggressive and a major threat to human health. Despite the significant improvement in patients' prognosis given the drug development efforts during the past several decades, many clinical questions still remain to be addressed such as efficacy when combining different therapeutic modalities, best treatment sequences, interindividual variability as well as resistance and potential coping strategies. To better answer these questions, we developed a mechanistic quantitative systems pharmacology model of the pathophysiology of HER2+ mBC that was extensively calibrated and validated against multiscale data to quantitatively predict and characterize the signal transduction and preclinical tumor growth kinetics under different therapeutic interventions. Focusing on the second-line treatment for HER2+ mBC, e.g., antibody-drug conjugates (ADC), small molecule inhibitors/TKI and chemotherapy, the model accurately predicted the efficacy of various drug combinations and dosing regimens at the in vitro and in vivo levels. Sensitivity analyses and subsequent heterogeneous phenotype simulations revealed important insights into the design of new drug combinations to effectively overcome various resistance scenarios in HER2+ mBC treatments. In addition, the model predicted a better efficacy of the new TKI plus ADC combination which can potentially reduce drug dosage and toxicity, while it also shed light on the optimal treatment ordering of ADC versus TKI plus capecitabine regimens, and these findings were validated by new in vivo experiments. Our model is the first that mechanistically integrates multiple key drug modalities in HER2+ mBC research and it can serve as a high-throughput computational platform to guide future model-informed drug development and clinical translation.

[Identification of Dredging Depths Based on Sediment Vertical Distribution Profiles of Total Nitrogen and Total Phosphorus and Their Adsorption-desorption Equilibria].

A dredging demonstration project in the Baiyangdian Lake included open waters and fishing ponds to reduce the internal release of nitrogen and phosphorus from bottom sediments. The dredging depth design was determined by both the sediment vertical distribution profile of total nitrogen and phosphorus, and the sediment adsorption-desorption equilibrium method. The determined dredging depths were very similar and coincident. The dredging depth for the demonstration area of open waters in Nanliuzhuang was identified as(50±10) cm; and the dredging depths for fishing ponds were(30±10) cm in both the Nanliuzhuang and Caiputai demonstration areas. The equilibrium nitrogen(NH4+-N) and phosphorus(SRP) concentrations at zero net sorption or desorption(ENC0 and EPC0) were significantly positively correlated with both exchangeable and total nitrogen and phosphorus in the sediments. The total nitrogen and phosphorus in the sediments were also used to predict the risk of their release from the bottom sediments to the overlying water column. The sediment layers with ENC0 and EPC0 values greater than the NH4+-N and SRP in the overlying water column indicated the sediments act as a source of dissolved nitrogen and phosphorus to the overlying water column in the Nanliuzhuang and Caiputai demonstration areas. Accordingly, the sediment layers with both total nitrogen concentrations greater than 750 mg·kg-1 and total phosphorus concentrations greater than 500 mg·kg-1 should be identified as dredging layers.

The anillin-related region of Bud4 is the major functional determinant for Bud4's function in septin organization during bud growth and axial bud site selection in budding yeast.

The anillin-related protein Bud4 of Saccharomyces cerevisiae is required for axial bud site selection by linking the axial landmark to the septins, which localize at the mother bud neck. Recent studies indicate that Bud4 plays a role in septin organization during cytokinesis. Here we show that Bud4 is also involved in septin organization during bud growth prior to cytokinesis, as bud4Δ shs1Δ cells displayed an elongated bud morphology and defective septin organization at 18°C. Bud4 overexpression also affected septin organization during bud growth in shs1Δ cells at 30°C. Bud4 was previously thought to associate with the septins via its central region, while the C-terminal anillin-related region was not involved in septin association. Surprisingly, we found that the central region of Bud4 alone targets to the bud neck throughout the cell cycle, unlike full-length Bud4, which localizes to the bud neck only during G2/M phase. We identified the anillin-related region to be a second targeting domain that cooperates with the central region for proper septin association. In addition, the anillin-related region could largely mediate Bud4's function in septin organization during bud growth and bud site selection. We show that this region interacts with the C terminus of Bud3 and the two segments depend on each other for association with the septins. Moreover, like the bud4Δ mutant, the bud3Δ mutant genetically interacts with shs1Δ and cdc12-6 mutants in septin organization, suggesting that Bud4 and Bud3 may cooperate in septin organization during bud growth. These observations provide new insights into the interaction of Bud4 with the septins and Bud3.