To establish bipolar attachments of microtubules to sister chromatids, an inner kinetochore subcomplex, the constitutive centromere-associated network (CCAN), is assembled on centromeric chromatin and recruits the microtubule-binding subcomplex called the KMN network. Since CCAN proteins CENP-C and CENP-T independently bind to the Mis12 complex (Mis12C) of KMN, it is difficult to evaluate the significance of each interaction in cells. Here, we demonstrate the molecular details of the CENP-T-Mis12C interaction using chicken DT40 cells lacking the CENP-C-Mis12C interaction. Using AlphaFold predictions combined with cell biological and biochemical analyses, we identified three binding surfaces of the CENP-T-Mis12C interaction, demonstrating that each interface is important for recruiting Mis12C to CENP-T in cells. This interaction, via three interaction surfaces, is cooperatively regulated by dual phosphorylation of Dsn1 (a Mis12C component) and CENP-T, ensuring a robust CENP-T-Mis12C interaction and proper mitotic progression. These findings deepen our understanding of kinetochore assembly in cells.
{"title":"Molecular details and phosphoregulation of the CENP-T-Mis12 complex interaction during mitosis in DT40 cells","authors":"Yusuke Takenoshita , Masatoshi Hara , Reiko Nakagawa , Mariko Ariyoshi , Tatsuo Fukagawa","doi":"10.1016/j.isci.2024.111295","DOIUrl":"10.1016/j.isci.2024.111295","url":null,"abstract":"<div><div>To establish bipolar attachments of microtubules to sister chromatids, an inner kinetochore subcomplex, the constitutive centromere-associated network (CCAN), is assembled on centromeric chromatin and recruits the microtubule-binding subcomplex called the KMN network. Since CCAN proteins CENP-C and CENP-T independently bind to the Mis12 complex (Mis12C) of KMN, it is difficult to evaluate the significance of each interaction in cells. Here, we demonstrate the molecular details of the CENP-T-Mis12C interaction using chicken DT40 cells lacking the CENP-C-Mis12C interaction. Using AlphaFold predictions combined with cell biological and biochemical analyses, we identified three binding surfaces of the CENP-T-Mis12C interaction, demonstrating that each interface is important for recruiting Mis12C to CENP-T in cells. This interaction, via three interaction surfaces, is cooperatively regulated by dual phosphorylation of Dsn1 (a Mis12C component) and CENP-T, ensuring a robust CENP-T-Mis12C interaction and proper mitotic progression. These findings deepen our understanding of kinetochore assembly in cells.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"27 12","pages":"Article 111295"},"PeriodicalIF":4.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142654813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.isci.2024.111299
Megan L. Stone , Hannah H. Lee , Edward M. Levine
It is advantageous to culture the ex vivo retina and other tissues at the air-liquid interface to allow for more efficient gas exchange. However, gene delivery to these cultures can be challenging. Electroporation is a fast and robust method of gene delivery, but typically requires submergence in liquid buffer for electrical current flow. We have developed a submergence-free electroporation technique that incorporates an agarose hydrogel disk between the positive electrode and retina. Inner retinal neurons and Müller glia are transfected with increased propensity toward Müller glia transfection after extended time in culture. We also observed an increase in BrdU incorporation in Müller glia following electrical stimulation, and variation in detection of transfected cells from expression vectors with different promoters. This method advances our ability to use ex vivo retinal tissue for genetic studies and should be adaptable for other tissues cultured at an air-liquid interface.
{"title":"Agarose hydrogel-mediated electroporation method for retinal tissue cultured at the air-liquid interface","authors":"Megan L. Stone , Hannah H. Lee , Edward M. Levine","doi":"10.1016/j.isci.2024.111299","DOIUrl":"10.1016/j.isci.2024.111299","url":null,"abstract":"<div><div>It is advantageous to culture the <em>ex vivo</em> retina and other tissues at the air-liquid interface to allow for more efficient gas exchange. However, gene delivery to these cultures can be challenging. Electroporation is a fast and robust method of gene delivery, but typically requires submergence in liquid buffer for electrical current flow. We have developed a submergence-free electroporation technique that incorporates an agarose hydrogel disk between the positive electrode and retina. Inner retinal neurons and Müller glia are transfected with increased propensity toward Müller glia transfection after extended time in culture. We also observed an increase in BrdU incorporation in Müller glia following electrical stimulation, and variation in detection of transfected cells from expression vectors with different promoters. This method advances our ability to use <em>ex vivo</em> retinal tissue for genetic studies and should be adaptable for other tissues cultured at an air-liquid interface.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"27 12","pages":"Article 111299"},"PeriodicalIF":4.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142654814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.isci.2024.111309
Héctor Tapia , Pedro Torres , Carlos Mateluna , Mónica Cáceres , Vicente A. Torres
Recent studies show that a group of salivary peptides, collectively known as histatins, are potent inducers of wound healing in both soft and hard tissues. Among these molecules, histatin-1 stands out for its ability to stimulate the repair of skin, oral mucosal, and osseous tissue. Remarkably, all these effects are associated with the capacity of histatin-1 to promote angiogenesis via inducing endothelial cell adhesion, migration, and signaling. These findings have opened new opportunities in the field of regenerative medicine, leading to an increasing number of articles and patents proposing therapeutic uses of histatin-1. However, this scenario raises a relevant concern regarding the appropriate use of these molecules, since, unlike the mode of action, little is known about the molecular mechanism by which they promote angiogenesis and wound healing. Recent studies shed light on the pharmacodynamics of histatin-1, by identifying the endothelial receptor that it binds and downstream signaling. This perspective will discuss current evidence on the role of histatins in wound healing and angiogenesis, emphasizing their impact on regenerative medicine.
{"title":"Histatins, proangiogenic molecules with therapeutic implications in regenerative medicine","authors":"Héctor Tapia , Pedro Torres , Carlos Mateluna , Mónica Cáceres , Vicente A. Torres","doi":"10.1016/j.isci.2024.111309","DOIUrl":"10.1016/j.isci.2024.111309","url":null,"abstract":"<div><div>Recent studies show that a group of salivary peptides, collectively known as histatins, are potent inducers of wound healing in both soft and hard tissues. Among these molecules, histatin-1 stands out for its ability to stimulate the repair of skin, oral mucosal, and osseous tissue. Remarkably, all these effects are associated with the capacity of histatin-1 to promote angiogenesis via inducing endothelial cell adhesion, migration, and signaling. These findings have opened new opportunities in the field of regenerative medicine, leading to an increasing number of articles and patents proposing therapeutic uses of histatin-1. However, this scenario raises a relevant concern regarding the appropriate use of these molecules, since, unlike the mode of action, little is known about the molecular mechanism by which they promote angiogenesis and wound healing. Recent studies shed light on the pharmacodynamics of histatin-1, by identifying the endothelial receptor that it binds and downstream signaling. This perspective will discuss current evidence on the role of histatins in wound healing and angiogenesis, emphasizing their impact on regenerative medicine.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"27 12","pages":"Article 111309"},"PeriodicalIF":4.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142654721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.isci.2024.111302
Han Yin , Fengyao Liu , Bingqing Bai , Quanjun Liu , Yuting Liu , Haochen Wang , Yu Wang , Yannis Yan Liang , Anbang Liu , Xueju Yu , Cheng Jiang , Chao Wu , Bo Kong , Jingjin Liu , Lan Guo , Hongwen Fei , Shuxia Wang , Wei Jiang , Huan Ma , Qingshan Geng
Mental stress-induced myocardial ischemia (MSIMI) is linked to a 2-fold increase in cardiovascular events, but its underlying myocardial blood flow (MBF) mechanisms remain underexplored. Using nitrogen-13-ammonia cardiac positron emission tomography-computed tomography (PET-CT) assessing myocardial perfusion defect and MBF under resting, mental stress (MS), adenosine stress (AS) conditions, angina with no obstructive coronary artery disease (ANOCA) women showed a significantly higher prevalence of MSIMI compared to age-matched healthy controls (36/84 vs. 1/42, p < 0.001). The MBFAS and rate-pressure product-corrected MBFMS were consistently lower, especially in the left anterior descending artery territory, in participants with increased perfusion defect scores under MS. The lowest values of restricted coronary flow reserve and corrected MBFMS in participants of ANOCA&MSIMI+ group indicated that impaired coronary microvascular function and mismatch between myocardial blood supply and demand together constitute the pathogenic mechanism of MSIMI in ANOCA population. These findings deepen our understanding of the pathophysiological mechanisms of MSIMI and confirm the long-standing hypothesis of the involvement of impaired coronary microvascular function.
{"title":"Myocardial blood flow mechanism of mental stress-induced myocardial ischemia in women with ANOCA","authors":"Han Yin , Fengyao Liu , Bingqing Bai , Quanjun Liu , Yuting Liu , Haochen Wang , Yu Wang , Yannis Yan Liang , Anbang Liu , Xueju Yu , Cheng Jiang , Chao Wu , Bo Kong , Jingjin Liu , Lan Guo , Hongwen Fei , Shuxia Wang , Wei Jiang , Huan Ma , Qingshan Geng","doi":"10.1016/j.isci.2024.111302","DOIUrl":"10.1016/j.isci.2024.111302","url":null,"abstract":"<div><div>Mental stress-induced myocardial ischemia (MSIMI) is linked to a 2-fold increase in cardiovascular events, but its underlying myocardial blood flow (MBF) mechanisms remain underexplored. Using nitrogen-13-ammonia cardiac positron emission tomography-computed tomography (PET-CT) assessing myocardial perfusion defect and MBF under resting, mental stress (MS), adenosine stress (AS) conditions, angina with no obstructive coronary artery disease (ANOCA) women showed a significantly higher prevalence of MSIMI compared to age-matched healthy controls (36/84 vs. 1/42, <em>p</em> < 0.001). The MBF<sub>AS</sub> and rate-pressure product-corrected MBF<sub>MS</sub> were consistently lower, especially in the left anterior descending artery territory, in participants with increased perfusion defect scores under MS. The lowest values of restricted coronary flow reserve and corrected MBF<sub>MS</sub> in participants of ANOCA&MSIMI+ group indicated that impaired coronary microvascular function and mismatch between myocardial blood supply and demand together constitute the pathogenic mechanism of MSIMI in ANOCA population. These findings deepen our understanding of the pathophysiological mechanisms of MSIMI and confirm the long-standing hypothesis of the involvement of impaired coronary microvascular function.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"27 12","pages":"Article 111302"},"PeriodicalIF":4.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142654806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.isci.2024.111297
Alexandra Langehennig-Peristenidou , Felix Felmy , Marina Scheumann
Graded call types predominate in species inhabiting open habitats with complex social systems, whereas discrete call types predominate in species with simple social systems living in closed habitats. This study aims to establish the vocal repertoire of Etruscan shrews, the smallest terrestrial mammal, which lives in pairs in closed habitats. Through various behavioral experiments, vocalizations were recorded and analyzed using unsupervised soft clustering, identifying four call types, one of which exhibited gradation. These calls were present in both pups and adults, showing age-related acoustic differences. One call type was observed during socio-positive behavior, with higher call rates during female-male interactions, while the others occurred during socio-negative contexts, with higher call rates for animals housed in pairs. Delivering the first detailed insight into Etruscan shrew vocal behavior, we demonstrated that the smallest terrestrial mammal possesses graded and discrete call types, regardless of its social system and habitat.
{"title":"Graded calls of the smallest terrestrial mammal, the Etruscan shrew, living in a closed habitat","authors":"Alexandra Langehennig-Peristenidou , Felix Felmy , Marina Scheumann","doi":"10.1016/j.isci.2024.111297","DOIUrl":"10.1016/j.isci.2024.111297","url":null,"abstract":"<div><div>Graded call types predominate in species inhabiting open habitats with complex social systems, whereas discrete call types predominate in species with simple social systems living in closed habitats. This study aims to establish the vocal repertoire of Etruscan shrews, the smallest terrestrial mammal, which lives in pairs in closed habitats. Through various behavioral experiments, vocalizations were recorded and analyzed using unsupervised soft clustering, identifying four call types, one of which exhibited gradation. These calls were present in both pups and adults, showing age-related acoustic differences. One call type was observed during socio-positive behavior, with higher call rates during female-male interactions, while the others occurred during socio-negative contexts, with higher call rates for animals housed in pairs. Delivering the first detailed insight into Etruscan shrew vocal behavior, we demonstrated that the smallest terrestrial mammal possesses graded and discrete call types, regardless of its social system and habitat.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"27 12","pages":"Article 111297"},"PeriodicalIF":4.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142654815","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.isci.2024.111301
Jun Zhu , Xiner Chen , Liuli Qin
We propose and demonstrate a structure consisting of graphene rings and square rings that enables broadband and tunable plasmon-induced transparency (PIT) effects. Through coupled Lorentz model analysis, we attribute the transmission window at 2.1 THz to the interference between the equipartitioned exciton resonance of the graphene ring pairs and the inductive-capacitive resonance of the graphene square ring pairs. We also investigate the effect of the variation of the rotation angle of the internal graphene square ring pair on the transmission characteristics. The structure not only achieves a maximum modulation depth (MDA) of 91%, insertion loss (IL) and extinction ratio (ER) of 0.3 dB and 10.94 dB, respectively, but also achieves a maximum detection sensitivity of 0.96 THz/refractive index unit (RIU). In contrast, this study achieves more than 90% modulation amplitude in the range of 0.3 THz with a simple design structure, providing new insights for research and applications in related fields.
{"title":"Novel terahertz optical switch based on PIT phenomenon and Lorentz theory","authors":"Jun Zhu , Xiner Chen , Liuli Qin","doi":"10.1016/j.isci.2024.111301","DOIUrl":"10.1016/j.isci.2024.111301","url":null,"abstract":"<div><div>We propose and demonstrate a structure consisting of graphene rings and square rings that enables broadband and tunable plasmon-induced transparency (PIT) effects. Through coupled Lorentz model analysis, we attribute the transmission window at 2.1 THz to the interference between the equipartitioned exciton resonance of the graphene ring pairs and the inductive-capacitive resonance of the graphene square ring pairs. We also investigate the effect of the variation of the rotation angle of the internal graphene square ring pair on the transmission characteristics. The structure not only achieves a maximum modulation depth (MDA) of 91%, insertion loss (IL) and extinction ratio (ER) of 0.3 dB and 10.94 dB, respectively, but also achieves a maximum detection sensitivity of 0.96 THz/refractive index unit (RIU). In contrast, this study achieves more than 90% modulation amplitude in the range of 0.3 THz with a simple design structure, providing new insights for research and applications in related fields.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"27 12","pages":"Article 111301"},"PeriodicalIF":4.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142654942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.isci.2024.111300
Huacui Wang , Yaobo Wu , Yangzheng Cao , Mingtao Liu , Xin Liu , Yue Liu , Binghe Liu
Lithium-ion batteries are currently widely used in various industries. Battery aging is inevitable, and it is also a key scientific issue in battery research. However, it is still lacking a comprehensive view of the aged battery from a mechanical perspective. This article aims to provide insight into the mechanical perspectives of the aged batteries. First, the morphologies of aged batteries were observed and measured from macro-to micro-scale. Second, the relationship between mechanical properties and the SOH of components and single batteries was quantified. Third, industrial CT and computational models were used to analyze the internal deformation of aged batteries. Finally, the swelling forces of aged batteries were investigated. The typical characteristics of swelling force were analyzed for various aged batteries, and mechanisms were revealed through experimental investigation, theoretical analysis, and numerical calculation. The results will help observe and reveal the aging mechanism of lithium batteries from a mechanical perspective.
{"title":"Investigate the changes of aged lithium iron phosphate batteries from a mechanical perspective","authors":"Huacui Wang , Yaobo Wu , Yangzheng Cao , Mingtao Liu , Xin Liu , Yue Liu , Binghe Liu","doi":"10.1016/j.isci.2024.111300","DOIUrl":"10.1016/j.isci.2024.111300","url":null,"abstract":"<div><div>Lithium-ion batteries are currently widely used in various industries. Battery aging is inevitable, and it is also a key scientific issue in battery research. However, it is still lacking a comprehensive view of the aged battery from a mechanical perspective. This article aims to provide insight into the mechanical perspectives of the aged batteries. First, the morphologies of aged batteries were observed and measured from macro-to micro-scale. Second, the relationship between mechanical properties and the SOH of components and single batteries was quantified. Third, industrial CT and computational models were used to analyze the internal deformation of aged batteries. Finally, the swelling forces of aged batteries were investigated. The typical characteristics of swelling force were analyzed for various aged batteries, and mechanisms were revealed through experimental investigation, theoretical analysis, and numerical calculation. The results will help observe and reveal the aging mechanism of lithium batteries from a mechanical perspective.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"27 12","pages":"Article 111300"},"PeriodicalIF":4.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142654881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.isci.2024.111303
Seohu Lee , Seongkwan Jang , Youngsu Cha
Touch is an inherent source of tactile sensation in everyday life, followed by vision and audition. For rich tactile feedback, multimodal haptic feedback is necessary because a single touch simultaneously excites multiple types of tactile receptors. In this paper, we present a soft wearable thermotouch haptic interface (T2HI) that simultaneously and independently provides touch and thermal stimulation using only one end-effector, the thermotouch haptic actuator (T2HA). A T2HA consists of a pneumatic-based touch haptic actuator and a thermoelectric-based thermal haptic stimulator. A novel design for the harmonious integration of the two different parts with wearable air pumps was proposed. Finally, the efficacy of the T2HI with virtual reality (VR) was evaluated by a user test. In VR, users manipulated a virtual object, and the corresponding touch and thermal feedback were provided. The T2HI demonstrated that multimodal haptic feedback significantly enhances the VR engagement of users compared to single-modal feedback.
{"title":"Soft wearable thermo+touch haptic interface for virtual reality","authors":"Seohu Lee , Seongkwan Jang , Youngsu Cha","doi":"10.1016/j.isci.2024.111303","DOIUrl":"10.1016/j.isci.2024.111303","url":null,"abstract":"<div><div>Touch is an inherent source of tactile sensation in everyday life, followed by vision and audition. For rich tactile feedback, multimodal haptic feedback is necessary because a single touch simultaneously excites multiple types of tactile receptors. In this paper, we present a soft wearable thermotouch haptic interface (T<sup>2</sup>HI) that simultaneously and independently provides touch and thermal stimulation using only one end-effector, the thermotouch haptic actuator (T<sup>2</sup>HA). A T<sup>2</sup>HA consists of a pneumatic-based touch haptic actuator and a thermoelectric-based thermal haptic stimulator. A novel design for the harmonious integration of the two different parts with wearable air pumps was proposed. Finally, the efficacy of the T<sup>2</sup>HI with virtual reality (VR) was evaluated by a user test. In VR, users manipulated a virtual object, and the corresponding touch and thermal feedback were provided. The T<sup>2</sup>HI demonstrated that multimodal haptic feedback significantly enhances the VR engagement of users compared to single-modal feedback.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"27 12","pages":"Article 111303"},"PeriodicalIF":4.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142654711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-01DOI: 10.1016/j.isci.2024.111296
Emilie Montellier , Nathanaël Lemonnier , Judith Penkert , Claire Freycon , Sandrine Blanchet , Amina Amadou , Florent Chuffart , Nicholas W. Fischer , Maria-Isabel Achatz , Arnold J. Levine , Catherine Goudie , David Malkin , Gaëlle Bougeard , Christian P. Kratz , Pierre Hainaut
Li-Fraumeni syndrome (LFS) is a heterogeneous predisposition to an individually variable spectrum of cancers caused by pathogenic TP53 germline variants. We used a clustering method to assign TP53 missense variants to classes based on their functional activities in experimental assays assessing biological p53 functions. Correlations with LFS phenotypes were analyzed using the public germline TP53 mutation database and validated in three LFS clinical cohorts. Class A carriers recapitulated all phenotypic traits of fully penetrant LFS, whereas class B carriers showed a slightly less penetrant form dominated by specific cancers, consistent with the notion that these classes identify variants with distinct functional properties. Class C displayed a lower lifetime cancer risk associated with attenuated LFS features, consistent with the notion that these variants have hypomorphic features. Class D carriers showed low lifetime cancer risks inconsistent with LFS definitions. This classification of TP53 variants provides insights into structural/functional features causing pathogenicity.
{"title":"Clustering of TP53 variants into functional classes correlates with cancer risk and identifies different phenotypes of Li-Fraumeni syndrome","authors":"Emilie Montellier , Nathanaël Lemonnier , Judith Penkert , Claire Freycon , Sandrine Blanchet , Amina Amadou , Florent Chuffart , Nicholas W. Fischer , Maria-Isabel Achatz , Arnold J. Levine , Catherine Goudie , David Malkin , Gaëlle Bougeard , Christian P. Kratz , Pierre Hainaut","doi":"10.1016/j.isci.2024.111296","DOIUrl":"10.1016/j.isci.2024.111296","url":null,"abstract":"<div><div>Li-Fraumeni syndrome (LFS) is a heterogeneous predisposition to an individually variable spectrum of cancers caused by pathogenic <em>TP53</em> germline variants. We used a clustering method to assign TP53 missense variants to classes based on their functional activities in experimental assays assessing biological p53 functions. Correlations with LFS phenotypes were analyzed using the public germline <em>TP53</em> mutation database and validated in three LFS clinical cohorts. Class A carriers recapitulated all phenotypic traits of fully penetrant LFS, whereas class B carriers showed a slightly less penetrant form dominated by specific cancers, consistent with the notion that these classes identify variants with distinct functional properties. Class C displayed a lower lifetime cancer risk associated with attenuated LFS features, consistent with the notion that these variants have hypomorphic features. Class D carriers showed low lifetime cancer risks inconsistent with LFS definitions. This classification of TP53 variants provides insights into structural/functional features causing pathogenicity.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"27 12","pages":"Article 111296"},"PeriodicalIF":4.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142654714","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-10-31DOI: 10.1016/j.isci.2024.111224
Chen Wu , Xiang Li , Shiyang Liu , Litong Yao , Tianyi He , Yusong Wang , Haoran Dong , Shuyi Niu , Mozhi Wang , Yingying Xu
Whether patients with de novo metastatic breast cancer (de novo MBC) benefit from primary tumor resection (PTR) is controversial, and the efficacy of treatment of primary tumor in patients with oligometastases is uncertain. A comprehensive search was conducted for studies published from January 1, 2008 to January 1, 2024 that compared PTR with no PTR for de novo MBC that quantified the extent of metastasis. Ten studies and 83,559 patients with de novo MBC were included. A meta-analysis showed a significant improvement in overall survival after PTR compared with no PTR (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.53–0.67; p < 0.00001). Similar results were seen in patients with 1 metastatic organ, ≤2 metastatic organs, and ≤3 metastatic organs. Oligometastatic patients are expected to be a beneficial subgroup for PTR in patients with MBC, especially when metastasis occurs in only one organ.
新发转移性乳腺癌（de novo metastatic breast cancer，de novo MBC）患者是否能从原发肿瘤切除术（PTR）中获益尚存争议，而对寡转移患者原发肿瘤的治疗效果也不确定。我们全面检索了2008年1月1日至2024年1月1日期间发表的研究，这些研究比较了对新发MBC进行原发肿瘤切除与不进行原发肿瘤切除的情况，并对转移范围进行了量化。共纳入了 10 项研究和 83,559 例新发 MBC 患者。一项荟萃分析显示，与不进行 PTR 相比，进行 PTR 后总生存率显著提高（危险比 [HR]，0.60；95% 置信区间 [CI]，0.53-0.67；P < 0.00001）。有 1 个转移器官、≤2 个转移器官和≤3 个转移器官的患者的结果相似。少转移患者有望成为PTR对MBC患者有益的亚组，尤其是当转移仅发生在一个器官时。
{"title":"Primary tumor resection in de novo metastatic breast cancer from an oligometastatic perspective: A systematic review and meta-analysis","authors":"Chen Wu , Xiang Li , Shiyang Liu , Litong Yao , Tianyi He , Yusong Wang , Haoran Dong , Shuyi Niu , Mozhi Wang , Yingying Xu","doi":"10.1016/j.isci.2024.111224","DOIUrl":"10.1016/j.isci.2024.111224","url":null,"abstract":"<div><div>Whether patients with <em>de novo</em> metastatic breast cancer (<em>de novo</em> MBC) benefit from primary tumor resection (PTR) is controversial, and the efficacy of treatment of primary tumor in patients with oligometastases is uncertain. A comprehensive search was conducted for studies published from January 1, 2008 to January 1, 2024 that compared PTR with no PTR for <em>de novo</em> MBC that quantified the extent of metastasis. Ten studies and 83,559 patients with <em>de novo</em> MBC were included. A meta-analysis showed a significant improvement in overall survival after PTR compared with no PTR (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.53–0.67; <em>p</em> < 0.00001). Similar results were seen in patients with 1 metastatic organ, ≤2 metastatic organs, and ≤3 metastatic organs. Oligometastatic patients are expected to be a beneficial subgroup for PTR in patients with MBC, especially when metastasis occurs in only one organ.</div></div>","PeriodicalId":342,"journal":{"name":"iScience","volume":"27 12","pages":"Article 111224"},"PeriodicalIF":4.6,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142654880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号