The identification of synergistic chemotherapeutic agents from a large pool of candidates is highly challenging. Here, we present a Ranking-system of Anti-Cancer Synergy (RACS) that combines features of targeting networks and transcriptomic profiles, and validate it on three types of cancer. Using data on human β-cell lymphoma from the Dialogue for Reverse Engineering Assessments and Methods consortium we show a probability concordance of 0.78 compared with 0.61 obtained with the previous best algorithm. We confirm 63.6% of our breast cancer predictions through experiment and literature, including four strong synergistic pairs. Further in vivo screening in a zebrafish MCF7 xenograft model confirms one prediction with strong synergy and low toxicity. Validation using A549 lung cancer cells shows similar results. Thus, RACS can significantly improve drug synergy prediction and markedly reduce the experimental prescreening of existing drugs for repurposing to cancer treatment, although the molecular mechanism underlying particular interactions remains unknown.
Transgenic mouse model with fluorescently labeled sperm has extensive application value. It is an auxiliary tool for investigating the mechanism of fertilization, especially for visualizing the oviductmigrating ability of sperm in vivo. Here, we produced transgenic mouse lines whose sperm were tagged with enhanced green fluorescent protein (EGFP) according to the previously described method. Polymerase chain reaction analysis of tail-tip genomic DNA identified 13 founders, of which 5 male founders produced offspring to form transgenic lines. We showed that EGFP was testis-specifically expressed, sharing similar expression pattern with endogenous acrosin. It has luminal side restricted distribution in seminiferous tubules and acrosomal aggregation in mature sperm. In addition, interstrain hybridization obtained Prss37 These results indicate that a transgenic mouse model with fluorescently labeled sperm has been successfully established and it is a useful tool for evaluating the oviduct-migrating ability of sperm.
Hermansky-Pudlak Syndrome (HPS) cases present with a variable degree of OCA and bleeding tendency. HPS is categorized into eleven types based on eleven causative genes, and disease severity varies among different types. By whole-exome sequencing performed on a family trio and Sanger sequencing of candidate variants, we identified a novel homozygous variant (NM_201280.3: c.181delC, p.Val61*) in BLOC1S5 in the patient who presents OCA and mild bleeding diathesis, and his healthy parents are heterozygous carriers. The variant can be considered pathogenic based on the guideline American College of Medical Genetics and Genomics, and the patient is proposed to be affected with HPS-11. In this study, we also explored bloc1s5 in zebrafish. bloc1s5 mRNA can be detected during early development of zebrafish. bloc1s5 knockdown zebrafish present with retinal hypopigmentation, thrombocytes loss and pericardial edema, and dll4/notch1 signaling and vascular integrity signaling are down-regulated at mRNA level in bloc1s5 morphants. The data from the first HPS-11 patient in Chinese population expand phenotypic and genotypic spectrum of HPS-11. Disruption of bloc1s5 in zebrafish recapitulates HPS-11-like phenotypes, and the potential signaling pathways associated with bloc1s5 are proposed. Altogether, this study may facilitate genetic counseling of HPS and investigation about BLOC1S5.
Background: Rubinstein-Taybi syndrome (RTS) is a rare, congenital, plurimalformative, and neurodevelopmental disorder. Previous studies have reported that large deletions contribute to more severe RTS phenotypes than those caused by CREBBP point mutations, suggesting a concurrent pathogenetic role of flanking genes, typical of contiguous gene syndromes, but the detailed genetics are unclear. Results: This study presented a rare case of Rubinstein-Taybi (RT) syndrome with serious cardiac abnormalities. Based on the clinical and genetic analysis of the patient, the ADCY9 gene deletion was highlighted as a plausible explanation of cardiac abnormalities. In adcy9 morphant zebrafish, cardiac malformation was observed. Immunofluorescence study disclosed increased macrophage migration and cardiac apoptosis. RNA sequencing in zebrafish model highlighted the changes of a number of genes, including increased expression of the mmp9 gene which encodes a matrix metalloproteinase with the main function to degrade and remodel extracellular matrix. Conclusions: In this study, we identified a plausible new candidate gene ADCY9 of CHD through the clinical and genetic analysis of a rare case of Rubinstein-Taybi (RT) syndrome with serious cardiac abnormalities. By functional study of zebrafish, we demonstrated that deletion of adcy9 is the causation for the cardiac abnormalities. Cardiac apoptosis and increased expression of the MMP9 gene are involved in the pathogenesis.
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