Disease Models & Mechanisms最新文献_第10页

Preclinical evaluation of targeted therapies for central nervous system metastases. 中枢神经系统转移瘤靶向疗法的临床前评估。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-09-01 Epub Date: 2024-09-30 DOI: 10.1242/dmm.050836

Alexander J Pfeil, Joshua D Hale, Tiger S Zhang, Kentaro Wakayama, Isao Miyazaki, Igor Odintsov, Romel Somwar

{"title":"Preclinical evaluation of targeted therapies for central nervous system metastases.","authors":"Alexander J Pfeil, Joshua D Hale, Tiger S Zhang, Kentaro Wakayama, Isao Miyazaki, Igor Odintsov, Romel Somwar","doi":"10.1242/dmm.050836","DOIUrl":"10.1242/dmm.050836","url":null,"abstract":"The central nervous system (CNS) represents a site of sanctuary for many metastatic tumors when systemic therapies that control the primary tumor cannot effectively penetrate intracranial lesions. Non-small cell lung cancers (NSCLCs) are the most likely of all neoplasms to metastasize to the brain, with up to 60% of patients developing CNS metastases during the disease process. Targeted therapies such as tyrosine kinase inhibitors (TKIs) have helped reduce lung cancer mortality but vary considerably in their capacity to control CNS metastases. The ability of these therapies to effectively target lesions in the CNS depends on several of their pharmacokinetic properties, including blood-brain barrier permeability, affinity for efflux transporters, and binding affinity for both plasma and brain tissue. Despite the existence of numerous preclinical models with which to characterize these properties, many targeted therapies have not been rigorously tested for CNS penetration during the discovery process, whereas some made it through preclinical testing despite poor brain penetration kinetics. Several TKIs have now been engineered with the characteristics of CNS-penetrant drugs, with clinical trials proving these efforts fruitful. This Review outlines the extent and variability of preclinical evidence for the efficacy of NSCLC-targeted therapies, which have been approved by the US Food and Drug Administration (FDA) or are in development, for treating CNS metastases, and how these data correlate with clinical outcomes.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"17 9","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11463968/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Sex-specific trisomic Dyrk1a-related skeletal phenotypes during development in a Down syndrome model. 在唐氏综合征小鼠模型的发育过程中，出现与三体 Dyrk1a 相关的骨骼表型的性别特异性。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-09-01 Epub Date: 2024-09-23 DOI: 10.1242/dmm.050914

Jonathan M LaCombe, Kourtney Sloan, Jared R Thomas, Matthew P Blackwell, Isabella Crawford, Flannery Bishop, Joseph M Wallace, Randall J Roper

{"title":"Sex-specific trisomic Dyrk1a-related skeletal phenotypes during development in a Down syndrome model.","authors":"Jonathan M LaCombe, Kourtney Sloan, Jared R Thomas, Matthew P Blackwell, Isabella Crawford, Flannery Bishop, Joseph M Wallace, Randall J Roper","doi":"10.1242/dmm.050914","DOIUrl":"10.1242/dmm.050914","url":null,"abstract":"Skeletal insufficiency affects all individuals with Down syndrome (DS) or trisomy 21 and may alter bone strength throughout development due to a reduced period of bone formation and early attainment of peak bone mass compared to those in typically developing individuals. Appendicular skeletal deficits also appear in males before females with DS. In femurs of male Ts65Dn DS model mice, cortical deficits were pronounced throughout development, but trabecular deficits and Dyrk1a overexpression were transitory until postnatal day (P) 30, when there were persistent trabecular and cortical deficits and Dyrk1a was trending toward overexpression. Correction of DS-related skeletal deficits by a purported DYRK1A inhibitor or through genetic means beginning at P21 was not effective at P30, but germline normalization of Dyrk1a improved male bone structure by P36. Trabecular and cortical deficits in female Ts65Dn mice were evident at P30 but subsided by P36, typifying periodic developmental skeletal normalizations that progressed to more prominent bone deficiencies. Sex-dependent differences in skeletal deficits with a delayed impact of trisomic Dyrk1a are important to find temporally specific treatment periods for bone and other phenotypes associated with trisomy 21.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11449447/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Drosophila model for mechanistic investigation of tau protein spread. 果蝇模型：tau 蛋白扩散的机理研究

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-09-01 Epub Date: 2024-10-01 DOI: 10.1242/dmm.050858

Kondalarao Bankapalli, Ruth E Thomas, Evelyn S Vincow, Gillian Milstein, Laura V Fisher, Leo J Pallanck

{"title":"A Drosophila model for mechanistic investigation of tau protein spread.","authors":"Kondalarao Bankapalli, Ruth E Thomas, Evelyn S Vincow, Gillian Milstein, Laura V Fisher, Leo J Pallanck","doi":"10.1242/dmm.050858","DOIUrl":"10.1242/dmm.050858","url":null,"abstract":"Brain protein aggregates are a hallmark of neurodegenerative disease. Previous work indicates that specific protein components of these aggregates are toxic, including tau (encoded by MAPT) in Alzheimer's disease and related tauopathies. Increasing evidence also indicates that these toxic proteins traffic between cells in a prion-like fashion, thereby spreading pathology from one brain region to another. However, the mechanisms involved in trafficking are poorly understood. We therefore developed a transgenic Drosophila model to facilitate rapid evaluation of candidate tau trafficking modifiers. Our model uses the bipartite Q system to drive co-expression of tau and GFP in the fly eye. We found age-dependent spread of tau into the brain, represented by detection of tau, but not of GFP. We also found that tau trafficking was attenuated upon inhibition of the endocytic factor dynamin (encoded by shi) or knockdown of glycogen synthase kinase-3β (GSK-3β, encoded by sgg). Further work revealed that dynamin promoted tau uptake in recipient tissues, whereas GSK-3β appeared to promote tau spread via direct phosphorylation of tau. Our robust and flexible system will promote the identification of tau-trafficking components involved in the pathogenesis of neurodegenerative diseases.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"17 9","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11463956/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Compromised COPII vesicle trafficking leads to glycogenic hepatopathy. COPII囊泡贩运功能受损导致斑马鱼糖源性肝病

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-09-01 Epub Date: 2024-09-30 DOI: 10.1242/dmm.050748

Yuxi Yang, Xue Zhang, Qingshun Zhao, Jingzi Zhang, Xin Lou

{"title":"Compromised COPII vesicle trafficking leads to glycogenic hepatopathy.","authors":"Yuxi Yang, Xue Zhang, Qingshun Zhao, Jingzi Zhang, Xin Lou","doi":"10.1242/dmm.050748","DOIUrl":"10.1242/dmm.050748","url":null,"abstract":"Being a vital cellular process, coat protein complex II (COPII) vesicle trafficking has been found to play a crucial role in liver metabolism. However, its functions and the underlying mechanisms in systemic metabolic homeostasis have not been fully understood. Here, with a newly identified gene trap zebrafish line (sec31anju221), we show that compromised COPII vesicle trafficking leads to biphasic abnormal hepatic metabolism. During the larval stage, deficiency of COPII-mediated trafficking leads to activation of the unfolded protein response and the development of hepatic steatosis. By using epistasis analysis, we found that the eIF2α-ATF4 pathway serves as the primary effector for liver steatosis. In adult sec31anju221 fish, the hepatosteatosis was reversed and the phenotype switched to glycogenic hepatopathy. Proteomic profiling and biochemical assays indicate that sec31anju221 fish are in a state of hypothyroidism. Moreover, our study shows that thyroid hormone treatment alleviates the metabolic defects. This study provides insights into processes of liver diseases associated with vesicle trafficking impairments and expands our understanding of the pathological interplay between thyroid and liver.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11463966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141975265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The highly metastatic 4T1 breast carcinoma model possesses features of a hybrid epithelial/mesenchymal phenotype. 高度转移的 4T1 乳腺癌模型具有上皮-间充质混合表型的特征。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-09-01 Epub Date: 2024-09-04 DOI: 10.1242/dmm.050771

Mary E Herndon, Mitchell Ayers, Katherine N Gibson-Corley, Michael K Wendt, Lori L Wallrath, Michael D Henry, Christopher S Stipp

{"title":"The highly metastatic 4T1 breast carcinoma model possesses features of a hybrid epithelial/mesenchymal phenotype.","authors":"Mary E Herndon, Mitchell Ayers, Katherine N Gibson-Corley, Michael K Wendt, Lori L Wallrath, Michael D Henry, Christopher S Stipp","doi":"10.1242/dmm.050771","DOIUrl":"10.1242/dmm.050771","url":null,"abstract":"Epithelial-mesenchymal transitions (EMTs) are thought to promote metastasis via downregulation of E-cadherin (also known as Cdh1) and upregulation of mesenchymal markers such as N-cadherin (Cdh2) and vimentin (Vim). Contrary to this, E-cadherin is retained in many invasive carcinomas and promotes collective cell invasion. To investigate how E-cadherin regulates metastasis, we examined the highly metastatic, E-cadherin-positive murine 4T1 breast cancer model, together with the less metastatic, 4T1-related cell lines 4T07, 168FARN and 67NR. We found that 4T1 cells display a hybrid epithelial/mesenchymal phenotype with co-expression of epithelial and mesenchymal markers, whereas 4T07, 168FARN, and 67NR cells display progressively more mesenchymal phenotypes in vitro that relate inversely to their metastatic capacity in vivo. Using RNA interference and constitutive expression, we demonstrate that the expression level of E-cadherin does not determine 4T1 or 4T07 cell metastatic capacity in mice. Mechanistically, 4T1 cells possess highly dynamic, unstable cell-cell junctions and can undergo collective invasion without E-cadherin downregulation. However, 4T1 orthotopic tumors in vivo also contain subregions of EMT-like loss of E-cadherin. Thus, 4T1 cells function as a model for carcinomas with a hybrid epithelial/mesenchymal phenotype that promotes invasion and metastasis.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11391819/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141893109","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction: Stimulating the sir2-spargel axis rescues exercise capacity and mitochondrial respiration in a Drosophila model of Barth syndrome. 更正：在巴特综合征果蝇模型中，刺激sir2-spargel轴可恢复运动能力和线粒体呼吸。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-09-01 Epub Date: 2024-09-26 DOI: 10.1242/dmm.052040

Deena Damschroder, Rubén Zapata-Pérez, Kristin Richardson, Frédéric M Vaz, Riekelt H Houtkooper, Robert Wessells

引用次数: 0

Activation of the heat shock response as a therapeutic strategy for tau toxicity. 激活热休克反应作为治疗 tau 毒性的一种策略。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-09-01 Epub Date: 2024-10-01 DOI: 10.1242/dmm.050635

Taylor R Stanley, Elizabeth M Otero, Amy L Knight, Aleen D Saxton, Xinxing Ding, Melissa Borgen, Brian C Kraemer, Karen S Kim Guisbert, Eric Guisbert

{"title":"Activation of the heat shock response as a therapeutic strategy for tau toxicity.","authors":"Taylor R Stanley, Elizabeth M Otero, Amy L Knight, Aleen D Saxton, Xinxing Ding, Melissa Borgen, Brian C Kraemer, Karen S Kim Guisbert, Eric Guisbert","doi":"10.1242/dmm.050635","DOIUrl":"10.1242/dmm.050635","url":null,"abstract":"Alzheimer's disease is associated with the misfolding and aggregation of two distinct proteins, beta-amyloid and tau. Previously, it has been shown that activation of the cytoprotective heat shock response (HSR) pathway reduces beta-amyloid toxicity. Here, we show that activation of the HSR is also protective against tau toxicity in a cell-autonomous manner. Overexpression of HSF-1, the master regulator of the HSR, ameliorates the motility defect and increases the lifespan of transgenic C. elegans expressing human tau. By contrast, RNA interference of HSF-1 exacerbates the motility defect and shortens lifespan. Targeting regulators of the HSR also affects tau toxicity. Additionally, two small-molecule activators of the HSR, Geranylgeranylacetone (GGA) and Arimoclomol (AC), have substantial beneficial effects. Taken together, this research expands the therapeutic potential of HSR manipulation to tauopathies and reveals that the HSR can impact both beta-amyloid and tau proteotoxicity in Alzheimer's disease.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":"17 9","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11463952/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142343409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Staphylococcus aureus lipid factors modulate melanoma cell clustering and invasion. 金黄色葡萄球菌脂质因子调节黑色素瘤细胞的聚集和侵袭

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-09-01 Epub Date: 2024-09-16 DOI: 10.1242/dmm.050770

Morgan A Giese, Gayathri Ramakrishnan, Laura H Steenberge, Jerome X Dovan, John-Demian Sauer, Anna Huttenlocher

引用次数: 0

Generation and characterization of a novel mouse model of Becker Muscular Dystrophy with a deletion of exons 52 to 55. 外显子 52 至 55 缺失的贝克尔肌肉营养不良症新型小鼠模型的生成和特征描述。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-08-05 DOI: 10.1242/dmm.050595

Lucie O M Perillat, Tatianna W Y Wong, Eleonora Maino, Abdalla Ahmed, Ori Scott, Elzbieta Hyatt, Paul Delgado-Olguin, Shagana Visuvanathan, Evgueni A Ivakine, Ronald D Cohn

{"title":"Generation and characterization of a novel mouse model of Becker Muscular Dystrophy with a deletion of exons 52 to 55.","authors":"Lucie O M Perillat, Tatianna W Y Wong, Eleonora Maino, Abdalla Ahmed, Ori Scott, Elzbieta Hyatt, Paul Delgado-Olguin, Shagana Visuvanathan, Evgueni A Ivakine, Ronald D Cohn","doi":"10.1242/dmm.050595","DOIUrl":"https://doi.org/10.1242/dmm.050595","url":null,"abstract":"Becker Muscular Dystrophy (BMD) is a rare X-linked recessive neuromuscular disorder frequently caused by in-frame deletions in the DMD gene that result in the production of a truncated, yet functional, dystrophin protein. The consequences of BMD-causing in-frame deletions on the organism are difficult to predict, especially in regard to long-term prognosis. Here, we employed CRISPR-Cas9 to generate a new Dmd del52-55 mouse model by deleting exons 52-55, resulting in a BMD-like in-frame deletion. To delineate the long-term effects of this deletion, we studied these mice over 52 weeks by performing histology and echocardiography analyses and assessing motor functions. Our results suggest that a truncated dystrophin is sufficient to maintain wildtype-like muscle and heart histology and functions in young mice. However, the truncated protein appears insufficient to maintain normal muscle homeostasis and protect against exercise-induced damage at 52 weeks. To further delineate the effects of this exon52-55 in-frame deletion, we performed RNA-Seq pre- and post-exercise and identified several differentially expressed pathways that reflect the abnormal muscle phenotype observed at 52 weeks in the BMD model.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141888756","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CCL2 signaling promotes skeletal muscle wasting in non-tumor and breast tumor models. C-C 趋化因子配体 2 信号传导促进了非肿瘤和乳腺肿瘤小鼠模型中骨骼肌的萎缩。

IF 4 3区医学

Disease Models & Mechanisms Pub Date : 2024-08-01 Epub Date: 2024-09-09 DOI: 10.1242/dmm.050398

Nadia Alissa, Wei Bin Fang, Marcela Medrano, Nick Bergeron, Yuuka Kozai, Qingting Hu, Chloe Redding, John Thyfault, Jill Hamilton-Reeves, Cory Berkland, Nikki Cheng

{"title":"CCL2 signaling promotes skeletal muscle wasting in non-tumor and breast tumor models.","authors":"Nadia Alissa, Wei Bin Fang, Marcela Medrano, Nick Bergeron, Yuuka Kozai, Qingting Hu, Chloe Redding, John Thyfault, Jill Hamilton-Reeves, Cory Berkland, Nikki Cheng","doi":"10.1242/dmm.050398","DOIUrl":"10.1242/dmm.050398","url":null,"abstract":"Despite advancements in treatment, approximately 25% of patients with breast cancer experience long-term skeletal muscle wasting (SMW), which limits mobility, reduces drug tolerance and adversely impacts survival. By understanding the underlying molecular mechanisms of SMW, we may be able to develop new strategies to alleviate this condition and improve the lives of patients with breast cancer. Chemokines are small soluble factors that regulate homing of immune cells to tissues during inflammation. In breast cancers, overexpression of C-C chemokine ligand 2 (CCL2) correlates with unfavorable prognosis. Elevated levels of CCL2 in peripheral blood indicate possible systemic effects of this chemokine in patients with breast cancer. Here, we investigated the role of CCL2 signaling on SMW in tumor and non-tumor contexts. In vitro, increasing concentrations of CCL2 inhibited myoblast and myotube function through C-C chemokine receptor 2 (CCR2)-dependent mechanisms involving JNK, SMAD3 and AMPK signaling. In healthy mice, delivery of recombinant CCL2 protein promoted SMW in a dose-dependent manner. In vivo knockdown of breast tumor-derived CCL2 partially protected against SMW. Overall, chronic, upregulated CCL2-CCR2 signaling positively regulates SMW, with implications for therapeutic targeting.","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":" ","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11413935/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141554350","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0