This paper proposes amodified formulation of the singular boundarymethod(SBM)by introducing the combined Helmholtz integral equation formulation(CHIEF)and the self-regularization technique to exterior acoustics.In the...This paper proposes amodified formulation of the singular boundarymethod(SBM)by introducing the combined Helmholtz integral equation formulation(CHIEF)and the self-regularization technique to exterior acoustics.In the SBM,the concept of the origin intensity factor(OIF)is introduced to avoid the singularities of the fundamental solutions.The SBM belongs to the meshless boundary collocation methods.The additional use of the CHIEF scheme and the self-regularization technique in the SBM guarantees the unique solution of the exterior acoustics accurately and efficiently.Consequently,by using the SBM coupled with the CHIEF scheme and the self-regularization technique,the accuracy of the numerical solution can be improved,especially near the corresponding internal characteristic frequencies.Several numerical examples of two-dimensional and threedimensional benchmark examples about exterior acoustics are used to verify the effectiveness and accuracy of the proposed method.The proposed numerical results are compared with the analytical solutions and the solutions obtained by the other numerical methods.展开更多
Endocrine-resistance remains a major challenge in estrogen receptorαpositive(ERα^(+))breast cancer(BC)treatment and constitutively active somatic mutations in ERαare a common mechanism.There is an urgent need to de...Endocrine-resistance remains a major challenge in estrogen receptorαpositive(ERα^(+))breast cancer(BC)treatment and constitutively active somatic mutations in ERαare a common mechanism.There is an urgent need to develop novel drugs with new mode of mechanism to fight endocrineresistance.Given aberrant ERαactivity,we herein report the identification of novel covalent selective estrogen receptor degraders(cSERDs)possessing the advantages of both covalent and degradation strategies.A highly potent cSERD 29c was identified with superior anti-proliferative activity than fulvestrant against a panel of ERa+breast cancer cell lines including mutant ERα.Crystal structure of ERα-29c complex alongside intact mass spectrometry revealed that 29c disrupted ERa protein homeostasis through covalent targeting C530 and strong hydrophobic interaction collied on H11,thus enforcing a unique antagonist conformation and driving the ERαdegradation.These significant effects of the cSERD on ERαhomeostasis,unlike typical ERαdegraders that occur directly via long side chains perturbing the morphology of H12,demonstrating a distinct mechanism of action(MoA).In vivo,29c showed potent antitumor activity in MCF-7 tumor xenograft models and low toxicity.This proof-of-principle study verifies that novel cSERDs offering new opportunities for the development of innovative therapies for endocrine-resistant BC.展开更多
基金supported by the National Science Fund of China(Grant No.12122205)the Six Talent Peaks Project in Jiangsu Province of China(Grant No.2019-KTHY-009).
文摘This paper proposes amodified formulation of the singular boundarymethod(SBM)by introducing the combined Helmholtz integral equation formulation(CHIEF)and the self-regularization technique to exterior acoustics.In the SBM,the concept of the origin intensity factor(OIF)is introduced to avoid the singularities of the fundamental solutions.The SBM belongs to the meshless boundary collocation methods.The additional use of the CHIEF scheme and the self-regularization technique in the SBM guarantees the unique solution of the exterior acoustics accurately and efficiently.Consequently,by using the SBM coupled with the CHIEF scheme and the self-regularization technique,the accuracy of the numerical solution can be improved,especially near the corresponding internal characteristic frequencies.Several numerical examples of two-dimensional and threedimensional benchmark examples about exterior acoustics are used to verify the effectiveness and accuracy of the proposed method.The proposed numerical results are compared with the analytical solutions and the solutions obtained by the other numerical methods.
基金supported by National Key R&D Program of China(2020YFA0908800,2021YFC2100300)National Natural Science Foundation of China(82273774,82073690,81773557,82173676,82103994)+1 种基金the Fundamental Research Funds for the Central Universities of China(2042022kf0056)the China Postdoctoral Science Foundation(2020M672435).
文摘Endocrine-resistance remains a major challenge in estrogen receptorαpositive(ERα^(+))breast cancer(BC)treatment and constitutively active somatic mutations in ERαare a common mechanism.There is an urgent need to develop novel drugs with new mode of mechanism to fight endocrineresistance.Given aberrant ERαactivity,we herein report the identification of novel covalent selective estrogen receptor degraders(cSERDs)possessing the advantages of both covalent and degradation strategies.A highly potent cSERD 29c was identified with superior anti-proliferative activity than fulvestrant against a panel of ERa+breast cancer cell lines including mutant ERα.Crystal structure of ERα-29c complex alongside intact mass spectrometry revealed that 29c disrupted ERa protein homeostasis through covalent targeting C530 and strong hydrophobic interaction collied on H11,thus enforcing a unique antagonist conformation and driving the ERαdegradation.These significant effects of the cSERD on ERαhomeostasis,unlike typical ERαdegraders that occur directly via long side chains perturbing the morphology of H12,demonstrating a distinct mechanism of action(MoA).In vivo,29c showed potent antitumor activity in MCF-7 tumor xenograft models and low toxicity.This proof-of-principle study verifies that novel cSERDs offering new opportunities for the development of innovative therapies for endocrine-resistant BC.
