The oncofetal mRNA-binding protein, IMP1 or insulin-like growth factor-2 mRNA-binding protein 2 (IGF2BP1), binds to and stabilizes c-Myc, β-TrCP1, and other oncogenic mRNAs, leading to increased expression of the proteins encoded by its target mRNAs. IMP1 is frequently overexpressed in cancer and is strongly correlated with a poor prognosis and reduced survival in melanoma, ovarian, breast, colon, and lung cancer. While IMP1 is an attractive anticancer drug target, there are no small molecule inhibitors of IMP1. A fluorescence anisotropy-based assay was used to screen 160,000 small molecules for their ability to inhibit IMP1 binding to fluorescein-labeled c-Myc mRNA. The small molecule, BTYNB, was identified as a potent and selective inhibitor of IMP1 binding to c-Myc mRNA. In cells, BTYNB downregulates several mRNA transcripts regulated by IMP1. BTYNB destabilizes c-Myc mRNA, resulting in downregulation of c-Myc mRNA and protein. BTYNB downregulates β-TrCP1 mRNA and reduces activation of nuclear transcriptional factors-kappa B (NF-κB). The oncogenic translation regulator, eEF2, emerged as a new IMP1 target mRNA, enabling BTYNB to inhibit tumor cell protein synthesis. BTYNB potently inhibited proliferation of IMP1-containing ovarian cancer and melanoma cells with no effect in IMP1-negative cells. Overexpression of IMP1 reversed BTYNB inhibition of cell proliferation. BTYNB completely blocked anchorage-independent growth of melanoma and ovarian cancer cells in colony formation assays. With its ability to target c-Myc and to inhibit proliferation of difficult-to-target melanomas and ovarian cancer cells, and with its unique mode of action, BTYNB is a promising small molecule for further therapeutic evaluation and mechanistic studies.

OBJECTIVES Antimicrobial stewardship programs target antimicrobial use within the inpatient care setting. However, most antimicrobials are prescribed at ambulatory sites. We aim to determine the appropriateness of the diagnosis and treatment of uncomplicated urinary tract infection (UTI) in children within the outpatient setting at our institution, and to evaluate the cost of antibiotic treatment in our patient cohort. METHODS This retrospective study was conducted by reviewing electronic records of patients aged 2 to 18 years diagnosed with uncomplicated UTI and treated with antibiotics in the outpatient setting from January 1, 2016, to April 30, 2016. Appropriate diagnosis was defined as confirmed UTI that included: pyuria (>5 white blood cells per high-power field or positive for leukocyte esterase), a positive urine culture (≥50,000 colony units/mL of a single uropathogen for a catheterized sample or ≥100,000 colony units/mL for a clean catch urine sample), and lower urinary tract symptoms. Treatment was considered appropriate if the patient was prescribed first-line antibiotic for the susceptible isolate (trimethoprim sulfamethoxazole, amoxicillinclavulanate, nitrofurantoin, and cephalexin), and if the appropriate dose was used. RESULTS We included 178 patients receiving a diagnosis of uncomplicated UTI and treated with antibiotics. Of these, 70% received an inappropriate diagnosis (n = 125). 58% (n= 72) of improperly diagnosed patients had polymicrobial growth in their urine cultures. Antibiotics prescribed mostly in this group were trimethoprim-sulfamethoxazole (53%, n = 66) and cephalexin (22%, n = 27). Only 30% of all included patients received an appropriate diagnosis (n = 53). Of all appropriate diagnosis patients (n = 53), 26% were treated inappropriately (n = 14) with either wide-spectrum antibiotics (n = 8) or with low calculated dose (n = 6). The estimated cost of antibiotic treatment for the inappropriate diagnosis group (n = 125) was $10,755.87. CONCLUSION Antimicrobial stewardship programs should target the pediatric outpatient setting and antibiograms should be developed. Education of providers about the appropriate diagnosis and treatment of uncomplicated UTI in children is essential for reducing the cost of inappropriate therapy.

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