Gene Transfer with AAV9-PHP.B Rescues Hearing in a Mouse Model of Usher Syndrome 3A and Transduces Hair Cells in a Non-human Primate.

Hereditary hearing loss often results from mutation of genes expressed by cochlear hair cells. Gene addition using AAV vectors has shown some efficacy in mouse models, but clinical application requires two additional advances. First, new AAV capsids must mediate efficient transgene expression in both inner and outer hair cells of the cochlea. Second, to have the best chance of clinical translation, these new vectors must also transduce hair cells in non-human primates. Here, we show that an AAV9 capsid variant, PHP.B, produces efficient transgene expression of a GFP reporter in both inner and outer hair cells of neonatal mice. We show also that AAV9-PHP.B mediates almost complete transduction of inner and outer HCs in a non-human primate. In a mouse model of Usher syndrome type 3A deafness (gene CLRN1), we use AAV9-PHP.B encoding Clrn1 to partially rescue hearing. Thus, we have identified a vector with promise for clinical treatment of hereditary hearing disorders, and we demonstrate, for the first time, viral transduction of the inner ear of a primate with an AAV vector

The logic of chemical synthesis

436 tr., X; 25 cm

Adverse Events and Safety of SARS-Cov2 Vaccines: What’s New and What’s Next

Just over one year following rollout of the first vaccines for coronavirus disease 2019 (COVID-19), 572 million doses have been administered in the United States. Comparatively to the number of vaccines administered, adverse effects such as anaphylaxis have been rare, and seemingly, the more serious the effect, the rarer the occurrence. Despite these adverse effects, there are few, if any, true contraindications to COVID-19 vaccination and most individuals recover without further sequelae. This review provides guidance for the allergist/immunologist regarding appropriate next steps based on patient’s known allergy history or adverse reaction after receipt of COVID-19 vaccine in order to assist in safe global immunization

Total Synthesis of Natural ProductsAt the Frontiers of Organic Chemistry /

XVI, 279 p. 271 illus., 48 illus. in color.onlin

Antitumor activity- and gene expression-based profiling of ecteinascidin Et 743 and phthalascidin Pt 650

AbstractBackground: Ecteinascidin 743 (Et 743) is a potent antitumor marine alkaloid currently undergoing phase II clinical trials. The synthetic analog phthalascidin (Pt 650), a designed structural analog of Et 743 displays in vitro potency comparable to Et 743. In this study, we used a panel of 36 human cancer cell lines, flow cytometry and oligonucleotide microarrays to analyze further these two compounds in a parallel fashion with regard to both antitumor activity (phenotype) and gene expression (genotype) bases.Results: The cancer panel experiment established that activity patterns of Et 743 and Pt 650 were essentially the same with their IC50 values ranging from pM to low nM. By means of flow cytometric cell cycle analysis using HCT116 cells, they were shown to disrupt S phase progression after a 12-h treatment at 2.0 nM, eventually resulting in the late S and G2/M accumulation at the 24-h time point. Array-based gene expression monitoring also demonstrated that the Et 743 and Pt 650 profiles were highly similar in two distinct cancer cell lines, HCT116 colon and MDA-MB-435 breast. Characteristic changes were observed in subsets of genes involved in DNA damage response, transcription and signal transduction. In HCT116 carrying the wild-type p53 tumor suppressor gene, the up-regulation of several p53-responsive genes was evident. Furthermore, a subset of genes encoding DNA-binding proteins to specific promoter regions (e.g. the CCAAT box) was down-regulated in both cell lines, suggesting one potential mode of action of this series of antitumor agents.Conclusion: A combination of gene expression analysis using oligonucleotide microarrays and flow cytometry confirms an earlier finding that Et 743 and Pt 650 have remarkably similar biological activities