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PNAS Papers on Gene Therapy Platform, Aspergillus Metabolome, Undernutrition Model Microbiome

Editor's Note: Some of the articles described below are not yet available at the PNAS site, but they are scheduled to be posted this week.

Researchers from the University of Zurich and the California Institute of Technology outline an approach for delivering protein-based treatments to specific cancer cell types using an adenovirus delivery system and cell surface markers, turning targeted cells into factories for producing and secreting antibodies or other therapeutics. The team applied its "shielded, retargeted adenovirus" (SHREAD) approach to a mouse model of HER2-overexpressing tumor cells treated with the anti-HER2 antibody trastuzumab (Genentech's Herceptin). When the authors assessed the murine mammary fat pad cells following SHREAD gene therapy, they found that it significantly bolstered the concentration of cancer-targeting antibodies in tumor cells. "This approach increases the tumor-to-bloodstream level of the model antibody 1,800-fold in comparison to direct administration," they report, noting that "this system could allow for the local production of highly potent drugs with greatly reduced risk of systemic toxicities."

A University of Wisconsin at Madison-led team investigates the "pan-secondary metabolome" in the Aspergillus flavus fungi model to better understand bioactive secondary metabolites that may serve as sources for pharmaceutical production in the future. The researchers identified pan-genomic biosynthetic gene clusters (BGCs) using genome sequence data for 94 A. flavus isolates, including a subset of population-specific BGCs, that they followed up on with the help of ultra-high-performance high-resolution mass spectrometry to profile secondary metabolite chemotypes and microevolution. "We demonstrate that even in one of the best-studied model fungi, the carcinogen-producing Aspergillus flavus, more than 25 percent of [secondary metabolite]-producing biosynthetic gene clusters are novel and/or show population-specific variants," they write, noting that "the organization of BGC diversity into population-specific patterns may sometimes result from ecologically important interactions and may inform evolutionary and etiological inferences of [secondary metabolite] capacities within a species."

Finally, a team from Washington University School of Medicine and elsewhere see ties between gut microbial community patterns, metabolic features, and undernutrition in a multi-generational pig model of diet restriction, a related feature-selection algorithm, and transplanted gut microbiome experiments in mice. With shotgun sequencing on 165 fecal samples from diet-restricted or full-fed pigs, the researchers focused on reduced nutrition-related microbial genes, including lower-than-usual levels of certain metabolic genes in the diet-restricted pigs and mice colonized with similar gut bugs. "Combining studies of farm animal microbiomes in gnotobiotic mice should help generate husbandry recommendations for promoting healthy growth of animals during this time of increasing food insecurity," they say, "and mandates to eliminate sub-therapeutic antibiotics for growth promotion."