Background:As a heterogeneous disease,breast cancer requires refined classification frameworks that can effectively guide targeted therapies.However,traditional methods fail to capture the comprehensive molecular insi...Background:As a heterogeneous disease,breast cancer requires refined classification frameworks that can effectively guide targeted therapies.However,traditional methods fail to capture the comprehensive molecular insights needed for this purpose.Methods:To comprehensively capture breast cancer heterogeneity,we employed integrative clustering that incorporates six molecular features from 670 breast cancer samples.Ten distinct clustering algorithms were combined to ensure robust subtype identification,and the identified subtypes were validated in four independent datasets.Subsequently,we constructed a survival support vector machine prognostic model based on key molecular features to enhance survival prediction and clinical applicability.Results:Five novel subtypes were identified:consensus subtypes 1–5(CS1–CS5).CS2 was an aggressive subtype with elevated TP53 mutation rates,high tumor mutational burden,and strong sensitivity to YM-155 and ispinesib.Conversely,CS5 exhibited stable genomics with enhanced nucleotide excision repair and favorable prognoses.CS2 and CS4 showed enriched immune checkpoint expression,indicating potential immunotherapy responsiveness,while CS1 and CS5 exhibited immune-cold profiles.The survival support vector machine model effectively predicted survival outcomes across independent datasets.Conclusions:The refined breast cancer classification framework developed in this research uncovers new insights into molecular heterogeneity,enhances risk stratification,and enables the identification of promising therapeutic targets.The potential of this framework to optimize personalized treatment strategies warrants further clinical validation.展开更多
Vestibular hair cells(HCs)in the inner ear,crucial for balance and spatial orientation,are classified into type I and type II subtypes,but the mechanisms regulating their differentiation remain unclear.In this study,w...Vestibular hair cells(HCs)in the inner ear,crucial for balance and spatial orientation,are classified into type I and type II subtypes,but the mechanisms regulating their differentiation remain unclear.In this study,we examined the role of Pou4f3,an important transcription factor,in vestibular HC differentiation using Pou4f3^(DTR/DTR)(deficient)and Pou4f3CreER/CreER(knockout)mouse models.In Pou4f3-deficient mice,the HC number decreased,and immature HCs failed to develop type I characteristics,indicating a developmental arrest.While type II HCs differentiated normally,Pou4f3 deficiency disrupted HC bundle formation and cell polarity.Findings from knockout models further confirmed the essential role of Pou4f3 in vestibular HC subtype specification.This study underscores the critical role of Pou4f3 in determining vestibular HC subtypes and offers insights into potential strategies for restoring vestibular function through HC regeneration.展开更多
基金supported by the National Natural Science Foundation of China(Grant No.:82560497,82260502,82272656)Guizhou Provincial Basic Research Program(Grant No.:Natural Science,MS[2025]-495)Talent Fund of Guizhou Provincial People’s Hospital(Grant No.:2022-33).
文摘Background:As a heterogeneous disease,breast cancer requires refined classification frameworks that can effectively guide targeted therapies.However,traditional methods fail to capture the comprehensive molecular insights needed for this purpose.Methods:To comprehensively capture breast cancer heterogeneity,we employed integrative clustering that incorporates six molecular features from 670 breast cancer samples.Ten distinct clustering algorithms were combined to ensure robust subtype identification,and the identified subtypes were validated in four independent datasets.Subsequently,we constructed a survival support vector machine prognostic model based on key molecular features to enhance survival prediction and clinical applicability.Results:Five novel subtypes were identified:consensus subtypes 1–5(CS1–CS5).CS2 was an aggressive subtype with elevated TP53 mutation rates,high tumor mutational burden,and strong sensitivity to YM-155 and ispinesib.Conversely,CS5 exhibited stable genomics with enhanced nucleotide excision repair and favorable prognoses.CS2 and CS4 showed enriched immune checkpoint expression,indicating potential immunotherapy responsiveness,while CS1 and CS5 exhibited immune-cold profiles.The survival support vector machine model effectively predicted survival outcomes across independent datasets.Conclusions:The refined breast cancer classification framework developed in this research uncovers new insights into molecular heterogeneity,enhances risk stratification,and enables the identification of promising therapeutic targets.The potential of this framework to optimize personalized treatment strategies warrants further clinical validation.
基金supported by the National Natural Science Foundation of China(82271159,82071049,82425018,and 82101219)the STI2030-Major Projects(2022ZD0205400).
文摘Vestibular hair cells(HCs)in the inner ear,crucial for balance and spatial orientation,are classified into type I and type II subtypes,but the mechanisms regulating their differentiation remain unclear.In this study,we examined the role of Pou4f3,an important transcription factor,in vestibular HC differentiation using Pou4f3^(DTR/DTR)(deficient)and Pou4f3CreER/CreER(knockout)mouse models.In Pou4f3-deficient mice,the HC number decreased,and immature HCs failed to develop type I characteristics,indicating a developmental arrest.While type II HCs differentiated normally,Pou4f3 deficiency disrupted HC bundle formation and cell polarity.Findings from knockout models further confirmed the essential role of Pou4f3 in vestibular HC subtype specification.This study underscores the critical role of Pou4f3 in determining vestibular HC subtypes and offers insights into potential strategies for restoring vestibular function through HC regeneration.
