Pathological MAPK activation–mediated lymphatic basement membrane disruption causes lymphangiectasia that is treatable with ravoxertinib

Janardhan, Harish P.; Dresser, Karen; Hutchinson, Lloyd; Trivedi, Chinmay M.

doi:10.1172/jci.insight.153033

Cited by 6 publications

(9 citation statements)

References 113 publications

(123 reference statements)

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“…Ravoxertinib has a critical effect on the inhibition of cancer cell growth. Studies have demonstrated that Ravoxertinib can reverse the nuclear-to-cytoplasmic localization defect of Nfatct in lymphatic dilatation and chylous accumulation during the development of the basement membrane, eventually improving the survival of endothelial KRAS-mutant newborn mice 38 . However, the relationship of this drug with adenomatous changes has not been reported and needs further investigation.…”

Section: Discussionmentioning

confidence: 99%

Common Key Genes in Differentiating Parathyroid Adenoma From Thyroid Adenoma

Lin

Mou

et al. 2023

Horm Metab Res

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Recent studies have demonstrated the close relationship between parathyroid adenoma(PA) and thyroid follicular adenoma(FTA). However, the underlying pathogenesis remains unknown. This study focused on exploring common pathogenic genes, as well as the pathogenesis of these two diseases, through bioinformatics methods. This work obtained PA and FTA datasets from the Integrated Gene Expression Database to identify the common differentially expressed genes (DEGs) of two diseases. The functions of the genes were investigated by GO and KEGG enrichment. The program CytoHubba was used to select the hub genes, while receiver operating characteristic curves were plotted to evaluate the predictive significance of the hub genes. The DGIbd database was used to identify gene-targeted drugs. This work detected a total of 77 DEGs. Enrichment analysis demonstrated that DEGs had activities of 3’,5'-cyclic AMP, and nucleotide phosphodiesterases and were associated with cell proliferation. NOS1, VWF, TGFBR2, CAV1, and MAPK1 were identified as hub genes after verification. The area under the curve of PA and FTA was > 0.7, and the hub genes participated in the Relaxin Signaling Pathway, focal adhesion, and other pathways. The construction of the mRNA-miRNA interaction network yielded 11 important miRNAs, while gene-targeting drug prediction identified four targeted drugs with possible effects. This bioinformatics study demonstrated that cell proliferation and tumor suppression, the hub genes co-occurring in PA and FTA, have important effects on the occurrence and progression of two diseases, which make them potential diagnostic biomarkers and therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Common Key Genes in Differentiating Parathyroid Adenoma From Thyroid Adenoma

Lin

Mou

et al. 2023

Horm Metab Res

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“…81 Patients with microcystic lymphatic malformations, often associated with venous malformation, benefit from pharmacological treatment targeting mTOR or MAPK signaling and a surgical approach. 84,110,111 For macrocystic lymphatic malformation, aspiration of the cystic content, injection of bleomycin or doxycycline, and optional surgical removal of exceeding skin show promising results. 112 Multifocal complex lymphatic anomalies, including generalized lymphatic anomaly, Kaposiform lymphangiomatosis, and channel-type lymphatic anomaly, affect multiple organs at birth.…”

Section: Arteriovenous Malformationsmentioning

confidence: 99%

Congenital Vascular and Lymphatic Diseases

Jung,

Trivedi

2024

Circulation Research

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Over the past several centuries, the integration of contemporary medical techniques and innovative technologies, like genetic sequencing, have played a pivotal role in enhancing our comprehension of congenital vascular and lymphatic disorders. Nonetheless, the uncommon and complex characteristics of these disorders, especially considering their formation during the intrauterine stage, present significant obstacles in diagnosis and treatment. Here, we review the intricacies of these congenital abnormalities, offering an in-depth examination of key diagnostic approaches, genetic factors, and therapeutic methods.

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“…Col4a indicates Collagen Type IV Alpha 1 Chain; Hspg2, Heparan Sulfate Proteoglycan 2; KRAS, KRAS Proto-Oncogene, GTPase; Lama4, Laminin Subunit Alpha 4; MAPK, Mitogen-Activated Protein Kinase 1; and Nid1, Nidogen 1. Adapted from Janardhan et al 22 Copyright ©2022.…”

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confidence: 99%

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confidence: 99%

“…Our recent studies demonstrated that gain-of-function mutation KRAS G12D and subsequent pathological activation of MAPK signaling disrupt lymphatic basement membrane composition and assembly, causing pulmonary lymphangiectasia, which promotes chylothorax limiting gas exchange in alveoli and neonatal survival (Figure ). 22 In 1787, Paolo Mascagni provided detailed illustrations of mesenteric and renal lymphatics in human cadavers. 9 Over the last hundred years, multiple investigations have identified and characterized the integrated nature of lymphatic function or dysfunction in various disease states including cardiac and renal diseases.…”

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confidence: 99%

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