2 research outputs found

    Proteolytic Unlocking of Ultrastable Twin-Acylhydrazone Linkers for Lysosomal Acid-Triggered Release of Anticancer Drugs

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    Targeted prodrugs exploiting cleavable linkers capable of responding to endogenous stimuli have increasingly been explored for cancer therapy. Successful application of these prodrug designs relies on the manipulation of both stability and responsiveness of the cleavable linkers, which, however, are difficult to be finely regulated, particularly for acid-responsive acylhydrazone bonds. Here we developed a new class of peptide-bridged twin-acylhydrazone linkers (PTA linkers) displaying both an ultrahigh stability and a rapid responsivenessî—¸highly stable in neutral and acidic conditions due to the effect of cooperativity between the two acylhydrazone bonds, easily cleavable in acidic conditions after enzymatically triggered unlocking of the two bonds. Moreover, our study shows the design of PTA-linked prodrugs and the proof-of-concept application of the PTA linkers for site-specific release of anticancer drugs into cancer cells

    A novel deletion downstream of the <i>PAX6</i> gene identified in a Chinese family with congenital aniridia

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    <p><b>Purpose</b>: Congenital aniridia, a severe bilateral panocular visual disorder, is an autosomal dominantly inherited eye anomaly. Mutations in the <i>paired box 6</i> gene (<i>PAX6</i>) have been shown to be responsible for congenital aniridia in most patients. The purpose of the present study was to report clinical features of a Chinese family with congenital aniridia and to screen novel genetic mutations for congenital aniridia.</p> <p><b>Methods</b>: All members of a three-generation family underwent comprehensive ophthalmic examination, and 8 of its 25 members were diagnosed with congenital aniridia. The proband was analyzed by exome sequencing and whole genome sequencing, and linkage analysis was performed for the family. The mutation was confirmed by direct DNA sequencing.</p> <p><b>Results</b>: Using Illumina’s Human Linkage-12 beadchip microarray (including 6090 SNPs) whole genome scan, the LOD score value showed that the interval on chromosome 11 between rs1389423 to rs910090 exhibited a strong linkage. A novel heterozygous 469 kb deletion mutation within the downstream region of <i>PAX6</i> (chr11:31189937–31659379) was identified in all affected family members, but not in unaffected family members or 2000 ethnically matched controls.</p> <p><b>Conclusion</b>: A novel deletion mutation was identified within the <i>PAX6</i> downstream region that results in congenital aniridia.</p
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