Research Roundup: November 2019

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Research Roundup: November 2019

Here are summaries of a selection of the papers published by GCB faculty in November 2019:

Cancer

Even though substantial time and resources have been put into cancer research, there is an extremely low success rate in translating preclinical discoveries into clinical practice. David Hsu is part of a team that is exploring comparative oncology – the study of cancers across species, often including veterinary patients that develop naturally-occurring cancers – which has the potential to enhance cost effectiveness and efficiency of pipelines for drug discovery and other cancer treatments. Read more

Sandeep Dave and team investigated all three subtypes of Burkitt lymphoma  using whole genome sequencing and transcriptome sequencing. The team also used experimental validation through CRISPR screening and mouse models to provide a better functional understanding of Burkitt lymphoma genetic drivers. Read more

Cancers often arise when normal cells accumulate multiple gene mutations that results in transformation. Oncogenic mutation of KRAS is identified in several cancer types, including soft tissue sarcomas. Understanding the pattern of genes co-mutated with Kras may provide novel insights into KRAS-mutant cancers with clinical implications. Charlie Gersbach was part of a team that performed an unbiased genome-wide CRISPR/Cas9 knockout screen in KrasG12D immortalized MEFs to search for genes that can cooperate with oncogenic Kras to drive growth in soft agar and in nude mice. They identified several candidate genes whose mutation results in transformation. Read more

Disease

In order to investigate whether childhood exposure to adverse experiences, stress and violence is associated with chronic stress-related inflammation in adults, Avshalom Caspi, Terrie Moffitt and team collected and analyzed plasma samples from members of the Environmental Risk Longitudinal Twin Study in the U.K. Read more

Doug Marchuk and team investigated the hypothesis that local somatic mutations seed the formation of hereditary hemorrhagic telangiectasia (HHT)-related telangiectasia in a genetic two-hit mechanism. Read more

Doug Marchuk and team worked to identify genes involved in cerebral infarctions to help provide a better understanding of the genetic risk factors of ischemic stroke. Read more

Doug Marchuk was part of team that showed that the gut barrier is a primary determinant of cerebral cavernous malformation (CCM) disease course that explains the increased severity of CCM disease associated with PDCD10 deficiency. Read more

Targets

Peptides and biologics provide unique opportunities to modulate intracellular targets not druggable by conventional small molecules. Most peptides and biologics are fused with cationic uptake moieties or formulated into nanoparticles to facilitate delivery, but these systems typically lack potency due to low uptake and/or entrapment and degradation in endolysosomal compartments. Because most delivery reagents comprise cationic lipids or polymers, there is a lack of reagents specifically optimized to deliver cationic cargo. Charlie Gersbach was part of a team that investigated the utility of the cytocompatible polymer poly(propylacrylic acid) (PPAA) to potentiate intracellular delivery of cationic biomacromolecules and nano-formulations. Read more

The spread of plasmid borne resistance enzymes in clinical Staphylococcus aureus isolates is rendering trimethoprim and iclaprim, both inhibitors of dihydrofolate reductase (DHFR), ineffective. Continued exploitation of these targets will require compounds that can broadly inhibit these resistance-conferring isoforms. Bruce Donald was part of a team that used a structure-based approach, to develop a novel class of ionized nonclassical antifolates (INCAs) that capture the molecular interactions that have been exclusive to classical antifolates. Read more

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