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MEN1611 is a novel orally bioavailable PI3K inhibitor currently in clinical development for patients with HER2‐positive (HER2+) PI3KCA mutated advanced/metastatic breast cancer (BC) in combination with trastuzumab (TZB). In this work, a translational model‐based approach to determine the minimum target exposure of MEN1611 in combination with TZB was applied. First, pharmacokinetic (PK) models for MEN1611 and TZB in mice were developed. Then, in vivo tumor growth inhibition (TGI) data from seven combination studies in mice xenograft models representative of the human HER2+ BC non‐responsive to TZB (alterations of the PI3K/AkT/mTOR pathway) were analyzed using a PK‐pharmacodynamic (PD) TGI model for co‐administration of MEN1611 and TZB. The established PK‐PD relationship was used to quantify the minimum effective MEN1611 concentration, as a function of TZB concentration, needed for tumor eradication in xenograft mice. Finally, a range of minimum effective exposures for MEN1611 were extrapolated to patients with BC, considering the typical steady‐state TZB plasma levels in patients with BC following three alternative regimens (i.v. 4 mg/kg loading dose +2 mg/kg q1w, i.v. 8 mg/kg loading dose +6 mg/kg q3w or s.c. 600 mg q3w). A threshold of about 2000 ng·h/ml for MEN1611 exposure associated with a high likelihood of effective antitumor activity in a large majority of patients was identified for the 3‐weekly and the weekly i.v. schedule for TZB. A slightly lower exposure (i.e., 25% lower) was found for the 3‐weekly s.c. schedule. This important outcome confirmed the adequacy of the therapeutic dose administered in the ongoing phase 1b B‐PRECISE‐01 study in patients with HER2+ PI3KCA mutated advanced/metastatic BC. [ABSTRACT FROM AUTHOR]

Coastal lagoons and brackish ponds are extremely dynamic and temporary ecosystems that follow natural changes throughout their geological history. The correct management of the lagoons ensures their integrity and proper functioning. For this reason, their ecological status should be surveyed for assessing the most appropriate strategies of use. In the present study, historical datasets collected in 2003–2004 are used to investigate the spatiotemporal variation in the species composition and community structure of the macrobenthos of the Tortolì Lagoon (Sardinia, Italy) and to assess their relationship with key environmental variables. Owing to the presence of a riverine runoff at a site and confined areas at some distance from the sea inlet, we hypothesize the marked spatiotemporal changes of the macrobenthic community consistent with the high environmental variability typical of coastal lagoons. The results show a surprisingly high benthic biodiversity for a medium-sized lagoon (250 ha), with 101 species unevenly distributed across the lagoon. The environmental variables did not explain the zonation of the macrobenthic community as that typically found along a lagoonal gradient, due to a marked marine influence. The sampling sites were in fact discriminated by the species distribution according to their ecological affinity; in particular, the most distinctive characteristics of the Tortolì Lagoon emerged from the strictly marine species that represented the most abundant group, consistently with the high marinization of the lagoon. Our results show that the Tortolì Lagoon constitutes a peculiar ecosystem within Mediterranean lagoons, departing from the classic confinement theory. [ABSTRACT FROM AUTHOR]