Severity: Warning
Message: file_get_contents(https://...@gmail.com&api_key=61f08fa0b96a73de8c900d749fcb997acc09): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
Filename: helpers/my_audit_helper.php
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File: /var/www/html/application/helpers/my_audit_helper.php
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Function: file_get_contents
File: /var/www/html/application/helpers/my_audit_helper.php
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Function: simplexml_load_file_from_url
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Function: getPubMedXML
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Function: pubMedSearch_Global
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Function: pubMedGetRelatedKeyword
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Function: require_once
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File: /var/www/html/application/helpers/my_audit_helper.php
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Function: _error_handler
File: /var/www/html/application/controllers/Detail.php
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Function: pubMedSearch_Global
File: /var/www/html/application/controllers/Detail.php
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Function: pubMedGetRelatedKeyword
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Function: require_once
Context: Pheochromocytoma and paraganglioma (PPGL) may appear as a complication of cyanotic congenital heart disease (CCHD-PPGL) with frequent EPAS1 mutations, suggesting a close link between EPAS1 mutations and tissue hypoxia in CCHD-PPGL pathogenesis.
Objective: Our aim is to further investigate the role of EPAS1 mutations in the hypoxia-driven mechanism of CCHD-PPGL pathogenesis, particularly focusing on metachronous and/or multifocal CCHD-PPGL tumors.
Methods: We performed whole-exome sequencing (WES) for somatic and germline mutations in 15 PPGL samples from 7 CCHD patients, including 3 patients with metachronous and/or multifocal tumors, together with an adrenal medullary hyperplasia (AMH) sample.
Results: We detected EPAS1 mutations in 15 out of 16 PPGL/AMH samples from 7 cases. Conspicuously, all EPAS1 mutations in each of 3 cases with multifocal or metachronous tumors were mutually independent and typical examples of parallel evolution, which is suggestive of strong positive selection of EPAS1-mutated clones. Compared to 165 The Cancer Genome Atlas non-CCHD-PPGL samples, CCHD-PPGL/AMH samples were enriched for 11p deletions (13/16) and 2p amplifications (4/16). Of particular note, the multiple metachronous PPGL tumors with additional copy number abnormalities developed 18 to 23 years after the resolution of hypoxemia, suggesting that CCHD-induced hypoxic environments are critical for positive selection of EPAS1 mutants in early life, but may no longer be required for development of PPGL in later life.
Conclusion: Our results highlight a key role of activated hypoxia-inducible factor 2α due to mutated EPAS1 in positive selection under hypoxic environments, although hypoxemia itself may not necessarily be required for the EPAS1-mutated clones to progress to PPGL.
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Source |
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http://dx.doi.org/10.1210/clinem/dgac362 | DOI Listing |
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