Selective Endothelial Hyperactivation of Oncogenic KRAS Induces Brain Arteriovenous Malformations in Mice DOI
Eun Su Park, Sehee Kim,

Shuning Huang

et al.

Annals of Neurology, Journal Year: 2021, Volume and Issue: 89(5), P. 926 - 941

Published: March 6, 2021

Brain arteriovenous malformations (bAVMs) are a leading cause of hemorrhagic stroke and neurological deficits in children young adults, however, no pharmacological intervention is available to treat these patients. Although more than 95% bAVMs sporadic without family history, the pathogenesis largely unknown, which may account for lack therapeutic options. KRAS mutations frequently observed cancer, recent unprecedented finding human offers new direction bAVM research. Using novel adeno-associated virus targeting brain endothelium (AAV-BR1), current study tested if endothelial KRASG12V mutation induces mice.Five-week-old mice were systemically injected with either AAV-BR1-GFP or -KRASG12V . At 8 weeks after AAV injection, formation characteristics addressed by histological molecular analyses. The effect MEK/ERK inhibition on -induced was determined treatment trametinib, US Food Drug Administration (FDA)-approved inhibitor.The viral-mediated overexpression induced bAVMs, composed tangled nidus mirroring distinctive morphology bAVMs. accompanied focal angiogenesis, intracerebral hemorrhages, altered vascular constituents, neuroinflammation, impaired sensory/cognitive/motor functions. Finally, we confirmed that growth inhibited trametinib treatment.Our innovative approach using AAV-BR1 confirms promote development via pathway, provides preclinical mouse model will be useful develop strategy patients bAVM. ANN NEUROL 2021;89:926-941.

Language: Английский

Small molecules in targeted cancer therapy: advances, challenges, and future perspectives DOI Creative Commons
Lei Zhong, Yueshan Li, Liang Xiong

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: May 31, 2021

Abstract Due to the advantages in efficacy and safety compared with traditional chemotherapy drugs, targeted therapeutic drugs have become mainstream cancer treatments. Since first tyrosine kinase inhibitor imatinib was approved enter market by US Food Drug Administration (FDA) 2001, an increasing number of small-molecule been developed for treatment malignancies. By December 2020, 89 antitumor FDA National Medical Products (NMPA) China. Despite great progress, anti-cancer still face many challenges, such as a low response rate drug resistance. To better promote development we conducted comprehensive review according target classification. We present all well important candidates clinical trials each target, discuss current provide insights perspectives research drugs.

Language: Английский

Citations

1176
Zebrafish disease models in drug discovery: from preclinical modelling to clinical trials DOI
E. Elizabeth Patton, Leonard I. Zon, David M. Langenau

et al.

Nature Reviews Drug Discovery, Journal Year: 2021, Volume and Issue: 20(8), P. 611 - 628

Published: June 11, 2021

Language: Английский

Citations

367
A review of mechanisms of disease across PIK3CA-related disorders with vascular manifestations DOI Creative Commons
Guillaume Canaud, Adrienne M. Hammill, Denise M. Adams

et al.

Orphanet Journal of Rare Diseases, Journal Year: 2021, Volume and Issue: 16(1)

Published: July 8, 2021

Abstract Background PIK3CA -related disorders include vascular malformations and overgrowth of various tissues that are caused by postzygotic, somatic variants in the gene encoding phosphatidylinositol-3-kinase (PI3K) catalytic subunit alpha. These mutations result activation PI3K/AKT/mTOR signaling pathway. The goals this review to provide education on underlying mechanism disease for group rare conditions summarize recent advancements understanding of, as well current emerging treatment options disorders. Main body spectrum (PROS), malformations, nonvascular lesions. Somatic activating (predominantly hotspots helical kinase domains PIK3CA, but also other domains), lead hyperactivation PI3K pathway, which results abnormal tissue growth. Diagnosis is complicated variability overlap phenotypes associated with should be performed clinicians required expertise along coordinated care from a multidisciplinary team. Although mosaicism presents challenges confirmation mutations, next-generation sequencing selection have improved detection. Clinical improvement, radiological response, patient-reported outcomes typically used assess response clinical studies patients disorders, objective assessment difficult using imaging (due heterogeneous nature these superimposed upon patient growth development). Despite their limitations, outcome tools may best suited gauge improvement. New therapeutic needed an alternative or supplement standard approaches such surgery sclerotherapy. Currently, there no systemic agents regulatory approval mTOR inhibitor sirolimus has been several years trials off label address symptoms. There under investigation act inhibitors target different components pathway including AKT (miransertib) alpha (alpelisib). Conclusion Management requires approach. Further ongoing targeting highly anticipated.

Language: Английский

Citations

108
Shaping the brain vasculature in development and disease in the single-cell era DOI Open Access
Thomas Wälchli, Jeroen Bisschop, Peter Carmeliet

et al.

Nature reviews. Neuroscience, Journal Year: 2023, Volume and Issue: 24(5), P. 271 - 298

Published: March 20, 2023

Language: Английский

Citations

77
Repurposing drugs to treat cardiovascular disease in the era of precision medicine DOI Open Access
Mena Abdelsayed, Eric J. Kort, Stefan Jovinge

et al.

Nature Reviews Cardiology, Journal Year: 2022, Volume and Issue: 19(11), P. 751 - 764

Published: May 23, 2022

Language: Английский

Citations

73
Transcriptomic Profiling Unveils EDN3+ Meningeal Fibroblasts as Key Players in Sturge‐Weber Syndrome Pathogenesis DOI Creative Commons

Daosheng Ai,

Tang Ming,

Xiaoli Li

et al.

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 8, 2025

Abstract Sturge‐Weber syndrome (SWS) is characterized by leptomeningeal vascular malformation, resulting in significant risks of life‐threatening seizures and strokes. The current absence specific treatments underscores the need to define molecular cellular mechanisms that drive progression SWS. Here, transcriptome 119 446 cells isolated from both malformed tissues peri‐lesion brains patients with SWS examined. This comprehensive analysis finds a complex landscape cell heterogeneity distinct substate associated evolution this disease are revealed. Notably, unique fibroblast cluster mechanism identified contribute development These findings not only expand understanding but also open up promising avenues for therapeutic interventions.

Language: Английский

Citations

2
High prevalence of KRAS/BRAF somatic mutations in brain and spinal cord arteriovenous malformations DOI Open Access
Tao Hong,

Yupeng Yan,

Jingwei Li

et al.

Brain, Journal Year: 2018, Volume and Issue: 142(1), P. 23 - 34

Published: Nov. 20, 2018

Brain and spinal arteriovenous malformations are congenital lesions causing intracranial haemorrhage or permanent disability especially in young people. We investigated whether the vast majority all brain associated with detectable tumour-related somatic mutations. In a cohort of 31 patients (21 10 malformations), tissue paired blood samples were analysed ultradeep next generation sequencing panel 422 common tumour genes to identify used droplet digital polymerase chain reaction confirm sequenced mutations additional low variant frequency The association mutation frequencies clinical features analysed. average depth was 1077 ± 298×. High prevalence (87.1%) KRAS/BRAF found no other replicated 81.0% (17 21) 100% (10 10) malformations. detected activating BRAF two novel KRAS (p.G12A p.S65_A66insDS) CNS for first time. negatively correlated nidus volumes (P = 0.038) 0.028) but not ages. Our findings support causative role overwhelming This pathway homogeneity high implies development targeted therapies RAS/RAF inhibitors without necessity genetic diagnosis.

Language: Английский

Citations

135
Genotype-Guided Medical Treatment of an Arteriovenous Malformation in a Child DOI
Ramrada Lekwuttikarn, Young Hee Lim,

Shehla Admani

et al.

JAMA Dermatology, Journal Year: 2018, Volume and Issue: 155(2), P. 256 - 256

Published: Dec. 19, 2018

Our website uses cookies to enhance your experience. By continuing use our site, or clicking "Continue," you are agreeing Cookie Policy | Continue JAMA Dermatology HomeNew OnlineCurrent IssueFor Authors Podcast Publications Network Open Cardiology Health Forum Internal Medicine Neurology Oncology Ophthalmology Otolaryngology–Head & Neck Surgery Pediatrics Psychiatry Archives of (1919-1959) JN Learning / CMESubscribeJobsInstitutions LibrariansReprints Permissions Terms Use Privacy Accessibility Statement 2023 American Medical Association. All Rights Reserved Search Archive Input Term Sign In Individual inCreate an Account Access through institution Purchase Options: Buy this article Rent Subscribe the journal

Language: Английский

Citations

112
Somatic Mutations in Vascular Malformations of Hereditary Hemorrhagic Telangiectasia Result in Bi-allelic Loss of ENG or ACVRL1 DOI Creative Commons
Daniel Snellings,

Carol J. Gallione,

Dewi Clark

et al.

The American Journal of Human Genetics, Journal Year: 2019, Volume and Issue: 105(5), P. 894 - 906

Published: Oct. 17, 2019

Language: Английский

Citations

108
The Pathogenesis of Port Wine Stain and Sturge Weber Syndrome: Complex Interactions between Genetic Alterations and Aberrant MAPK and PI3K Activation DOI Open Access
Vi Nguyen,

Marcelo Hochman,

Martín C. Mihm

et al.

International Journal of Molecular Sciences, Journal Year: 2019, Volume and Issue: 20(9), P. 2243 - 2243

Published: May 7, 2019

Port wine stain (PWS) is a congenital vascular malformation involving human skin. Approximately 15–20% of children facial PWS the ophthalmic (V1) trigeminal dermatome are at risk for Sturge Weber syndrome (SWS), neurocutaneous disorder with malformations in cerebral cortex on same side lesions. Recently, evidence has surfaced that advanced our understanding pathogenesis PWS/SWS, including discoveries somatic genetic mutations (GNAQ, PI3K), MAPK and PI3K aberrant activations, molecular phenotypes endothelial cells. In this review, we summarize current knowledge etiology pathology PWS/SWS based activation and/or contributes to malformations, as well potential futuristic treatment approaches targeting these aberrantly dysregulated signaling pathways. Current data support that: (1) multifactorial entire physiological structure skin; (2) should be pathoanatomically re-defined “a resulting from differentiation-impaired cells progressive dilatation immature venule-like vasculatures”; (3) dysregulation during embryonic development plays part progression PWS/SWS; (4) sporadic low frequency mutations, such GNAQ, PI3K, work team players but not lone wolf, contributing phenotypes. We also address many crucial questions yet answered future research investigations.

Language: Английский

Citations

105