The
parasitic disease onchocerciasis is the second leading cause of preventable
blindness, afflicting more than 18 million people worldwide. Despite
an available treatment, ivermectin, and control efforts by the World
Health Organization, onchocerciasis remains a burden in many regions.
With an estimated 120 million people living in areas at risk of infection,
efforts are now shifting from prevention to surveillance and elimination.
The lack of a robust, point-of-care diagnostic for an active Onchocerca infection has been a limiting factor in these
efforts. Previously, we reported the discovery of the biomarker N-acetyl-tyramine-O-glucuronide (NATOG)
in human urine samples and its ability to track treatment progression
between medicated patients relative to placebo; we also established
its capability to monitor disease burden in a jird model. NATOG is
a human-produced metabolite of tyramine, which itself is produced
as a nematode neurotransmitter. The ability of NATOG to distinguish
between active and past infection overcomes the limitations of antibody
biomarkers and PCR methodologies. Lateral flow immunoassay (LFIA)
diagnostics offer the versatility and simplicity to be employed in
the field and are inexpensive enough to be utilized in large-scale
screening efforts. Herein, we report the development and assessment
of a NATOG-based urine LFIA for onchocerciasis, which accurately identified
85% of analyzed patient samples (N = 27).
Choroid plexus carcinoma (CPC) is a rare brain tumor that occurs most commonly in very young children and has a dismal prognosis despite intensive therapy. Improved outcomes for patients with CPC depend on a deeper understanding of the mechanisms underlying the disease. Here we developed transgenic models of CPCs by activating the Myc oncogene and deleting the Trp53 tumor suppressor gene in murine neural stem cells or progenitors. Murine CPC resembled their human counterparts at a histologic level, and like the hypodiploid subset of human CPC, exhibited multiple wholechromosome losses, particularly of chromosomes 8, 12, and 19. Analysis of murine and human CPC gene expression profiles and copy number changes revealed altered expression of genes involved in cell cycle, DNA damage response, and cilium function. High-throughput drug screening identified small molecule inhibitors that decreased the viability of CPC. These models will be valuable tools for understanding the biology of choroid plexus tumors and for testing novel approaches to therapy. Significance: This study describes new mouse models of choroid plexus carcinoma and uses them to investigate the biology and therapeutic responsiveness of this highly malignant pediatric brain tumor.
MYC is a key transcriptional regulator involved in cellular proliferation and has established roles in transcriptional elongation and initiation, microRNA regulation, apoptosis, and pluripotency. Despite this prevalence, functional chemical probes of MYC function at the protein level have been limited. Previously, we discovered 5a, that binds to MYC with potency and specificity, downregulates the transcriptional activities of MYC and shows efficacy in vivo. However, this scaffold posed intrinsic pharmacokinetic liabilities, namely, poor solubility that precluded biophysical interrogation. Here, we developed a screening platform based on field-effect transistor analysis (Bio-FET), surface plasmon resonance (SPR), and a microtumor formation assay to analyze a series of new compounds aimed at improving these properties. This blind SAR campaign has produced a new lead compound of significantly increased in vivo stability and solubility for a 40-fold increase in exposure. This probe represents a significant advancement that will not only enable biophysical characterization of this interaction and further SAR, but also contribute to advances in understanding of MYC biology.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.