6 research outputs found
Numerical modelling of a loudspeaker sound radiation and its dynamic interaction with the host structure
No full textLoudspeakers play a key role in defining the sound field and quality in various environments. Their mounting on structures with different dynamic properties affects acoustic radiation. This study presents an innovative approach that combines the equivalent sources method (ESM) with dynamic considerations to model the interaction between the loudspeaker and its support. The model decouples the loudspeaker's acoustic emission from the host structure's radiation, allowing simulations in different configurations without re-synthesizing the equivalent sources, a limitation of traditional ESM. The approach is tested on a loudspeaker mounted on a dedicated test rig with adjustable dynamic properties to measure acoustic emission under varying conditions. To contextualize its performance, the model is benchmarked against the widely used Thiele-Small model for loudspeaker simulation in complex environments. Results show that the proposed model outperforms traditional methods in predicting sound pressure and directivity, providing a reliable tool for simulating loudspeaker behavior in complex scenarios. Its simplicity and versatility make it suitable for various numerical simulation applications
Experimental analysis of a car loudspeaker model based on imposed vibration velocity: effect of membrane discretization
No full textNowadays, the research about the improvement of the interior sound quality of road vehicles is a relevant task.
The cabin is an acoustically challenging environment due to the complex geometry, the different acoustic
properties of the materials of cabin components and the presence of audio systems based on multiple loudspeaker
units. This paper aims at presenting a simplified modelling approach designed to introduce the boundary condition
imposed by a loudspeaker to the cabin system in the context of virtual acoustic analysis. The proposed model is
discussed and compared with experimental measurements obtained from a test-case loudspeaker
Antitumor activity of the PI3K δ-sparing inhibitor MEN1611 in PIK3CA mutated, trastuzumab-resistant HER2 + breast cancer
No full textPurpose: Dysregulation of the PI3K pathway is one of the most common events in breast cancer. Here we investigate the activity of the PI3K inhibitor MEN1611 at both molecular and phenotypic levels by dissecting and comparing its profile and efficacy in HER2 + breast cancer models with other PI3K inhibitors. Methods: Models with different genetic backgrounds were used to investigate the pharmacological profile of MEN1611 against other PI3K inhibitors. In vitro studies evaluated cell viability, PI3K signaling, and cell death upon treatment with MEN1611. In vivo efficacy of the compound was investigated in cell line- and patient-derived xenografts models. Results: Consistent with its biochemical selectivity, MEN1611 demonstrated lower cytotoxic activity in a p110δ-driven cellular model when compared to taselisib, and higher cytotoxic activity in the p110β-driven cellular model when compared to alpelisib. Moreover, MEN1611 selectively decreased the p110α protein levels in PIK3CA mutated breast cancer cells in a concentration- and proteasome-dependent manner. In vivo, MEN1611 monotherapy showed significant and durable antitumor activity in several trastuzumab-resistant PIK3CA-mutant HER2 + PDX models. The combination of trastuzumab and MEN1611 significantly improved the efficacy compared to single agent treatment. Conclusions: The profile of MEN1611 and its antitumoral activity suggest an improved profile as compared to pan-inhibitors, which are limited by a less than ideal safety profile, and isoform selective molecules, which may potentially promote development of resistance mechanisms. The compelling antitumor activity in combination with trastuzumab in HER2 + trastuzumab-resistant, PIK3CA mutated breast cancer models is at the basis of the ongoing B-Precise clinical trial (NCT03767335)
Antitumor activity of the PI3K δ-sparing inhibitor MEN1611 in PIK3CA mutated, trastuzumab-resistant HER2 + breast cancer
No full textPI3K inhibitor; PIK3CA mutations; Trastuzumab resistanceInhibidor de PI3K; Mutacions PIK3CA; Resistència al trastuzumabInhibidor de PI3K; Mutaciones PIK3CA; Resistencia a trastuzumabPurpose
Dysregulation of the PI3K pathway is one of the most common events in breast cancer. Here we investigate the activity of the PI3K inhibitor MEN1611 at both molecular and phenotypic levels by dissecting and comparing its profile and efficacy in HER2 + breast cancer models with other PI3K inhibitors.
Methods
Models with different genetic backgrounds were used to investigate the pharmacological profile of MEN1611 against other PI3K inhibitors. In vitro studies evaluated cell viability, PI3K signaling, and cell death upon treatment with MEN1611. In vivo efficacy of the compound was investigated in cell line- and patient-derived xenografts models.
Results
Consistent with its biochemical selectivity, MEN1611 demonstrated lower cytotoxic activity in a p110δ-driven cellular model when compared to taselisib, and higher cytotoxic activity in the p110β-driven cellular model when compared to alpelisib. Moreover, MEN1611 selectively decreased the p110α protein levels in PIK3CA mutated breast cancer cells in a concentration- and proteasome-dependent manner. In vivo, MEN1611 monotherapy showed significant and durable antitumor activity in several trastuzumab-resistant PIK3CA-mutant HER2 + PDX models. The combination of trastuzumab and MEN1611 significantly improved the efficacy compared to single agent treatment.
Conclusions
The profile of MEN1611 and its antitumoral activity suggest an improved profile as compared to pan-inhibitors, which are limited by a less than ideal safety profile, and isoform selective molecules, which may potentially promote development of resistance mechanisms. The compelling antitumor activity in combination with trastuzumab in HER2 + trastuzumab-resistant, PIK3CA mutated breast cancer models is at the basis of the ongoing B-Precise clinical trial (NCT03767335).This work was supported by Regione Lazio, POR FESR 2014–2020 Bando “Life 2020_Progetti. integrati” for the project “PISTA (PI3K for Solid Tumor therApy)” (CUP F57H18000070007)
Abstract PS18-13: Men1611 is a pi3k α/β selective and δ sparing inhibitor with long-lasting antitumor activity in different genetic backgrounds of pik3ca mutant breast cancer models
No full textComparison of baseline patient characteristics in phase 1 and phase 2/3 clinical trials for anticancer treatments
No full textAbstract Background Characteristics of patients significantly differ between registrational clinical trials (CTs) and Italian real-world practice, with older median age, higher elderly (≥ 65) rate and worse performance status (PS) in the latter, without imbalance in female rate. We compared the same characteristics between registrational phase 2/3 and phase 1 CTs. Methods Data on age, sex and PS were extracted from European Public Assessment Reports of European Medicines Agency. Weighted means and standard deviations were calculated in both groups and differences were described overall, by cancer type and drug class. Results We collected 103 phase 2/3 and 111 phase 1 CTs, supporting 97 therapeutic indications. Age and sex were compared in 59 indications. Mean median age (SD) was 60.7 (5.1) years in phase 2/3 and 59.7 (5.6) years in phase 1 (p = 0.051). Age difference was greater for skin and breast cancer; no heterogeneity emerged among drug classes. Mean female rate was not statistically significantly lower in phase 2/3 than phase 1 CTs overall, (mean difference − 4.9%, p = 0.999); difference was greater for skin and upper-gastrointestinal cancers and for cytotoxic agents. Mean PS > 1 rate, compared in 47 indications, was similar in phase 2/3 [2.3% (4.7)] and phase 1 [1.8% (3.5)] (p = 0.374); difference was greater for colorectal cancer and cytotoxic agents. Conclusions We found no statistically significant difference in age, sex and PS between patients in phase 2/3 and corresponding phase 1 CTs for anticancer treatments. Therefore, patient selection in phase 1 trials appears crucial, considering its potential impact in later development phases
