RESUMEN
KRAS gain-of-function mutations are frequently observed in sporadic arteriovenous malformations. The mechanisms underlying the progression of such KRAS-driven malformations are still incompletely understood, and no treatments for the condition are approved. Here, we show the effectiveness of sotorasib, a specific KRAS G12C inhibitor, in reducing the volume of vascular malformations and improving survival in two mouse models carrying a mosaic Kras G12C mutation. We then administered sotorasib to two adult patients with severe KRAS G12C-related arteriovenous malformations. Both patients had rapid reductions in symptoms and arteriovenous malformation size. Targeting KRAS G12C appears to be a promising therapeutic approach for patients with KRAS G12C-related vascular malformations. (Funded by the European Research Council and others.).
Asunto(s)
Malformaciones Arteriovenosas , Proteínas Proto-Oncogénicas p21(ras) , Animales , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Malformaciones Arteriovenosas/diagnóstico , Malformaciones Arteriovenosas/diagnóstico por imagen , Malformaciones Arteriovenosas/tratamiento farmacológico , Malformaciones Arteriovenosas/genética , Modelos Animales de Enfermedad , Mutación con Ganancia de Función , Mutación , Piperazinas/uso terapéutico , Proteínas Proto-Oncogénicas p21(ras)/genética , Piridinas/uso terapéutico , Pirimidinas , Fármacos Cardiovasculares/uso terapéutico , Adulto JovenRESUMEN
A global tropical cyclone precipitation dataset covering the period from January 1979 to February 2023 is presented. Global precipitation estimates were taken from the newly developed high-resolution Multi-Source Weighted-Ensemble Precipitation, version 2 (MSWEP V2) and TC tracks were obtained from the International Best Track Archive for Climate Stewardship (IBTrACS) dataset. This Global Multi-Source Tropical Cyclone Precipitation (MSTCP) dataset is comprised of two main products and files in the format of tables: the main and profile datasets. The main file provides various TCP statistics per TC track, including mean and maximum precipitation rates over a fixed and symmetrical radius of 500 km. The profile dataset comprises the azimuthally averaged precipitation every 10-km away from the center of each storm (until 500 km). The case study of Hurricane Harvey is used to show that MSWEP estimates agree well with another commonly used satellite product. The main statistics of the dataset are analyzed as well, including the differences in the dataset metrics for each of the six TC basins and for each Saffir-Simpson category for storm intensity.
RESUMEN
Recent advances in genetic sequencing are transforming our approach to rare-disease care. Initially identified in cancer, gain-of-function mutations of the PIK3CA gene are also detected in malformation mosaic diseases categorized as PIK3CA-related disorders (PRDs). Over the past decade, new approaches have enabled researchers to elucidate the pathophysiology of PRDs and uncover novel therapeutic options. In just a few years, owing to vigorous global research efforts, PRDs have been transformed from incurable diseases to chronic disorders accessible to targeted therapy. However, new challenges for both medical practitioners and researchers have emerged. Areas of uncertainty remain in our comprehension of PRDs, especially regarding the relationship between genotype and phenotype, the mechanisms underlying mosaicism, and the processes involved in intercellular communication. As the clinical and biological landscape of PRDs is constantly evolving, this review aims to summarize current knowledge regarding PIK3CA and its role in nonmalignant human disease, from molecular mechanisms to evidence-based treatments. Expected final online publication date for the Annual Review of Genomics and Human Genetics, Volume 25 is August 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.