Discovery and Optimization of N-Arylated Tetracyclic Dicarboximides That Target Primary Glioma Stem-like Cells.

We recently discovered a novel N-aryl tetracyclic dicarboximide MM0299 () with robust activity against glioma stem-like cells that potently and selectively inhibits lanosterol synthase leading to the accumulation of the toxic shunt metabolite 24(),25-epoxycholesterol. Herein, we delineate a systematic and comprehensive SAR study that explores the structural space surrounding the N-aryl tetracyclic dicarboximide scaffold. A series of 100 analogs were synthesized and evaluated for activity against the murine glioma stem-like cell line Mut6 and for metabolic stability in mouse liver S9 fractions.

Interaction with B-type lamin reveals the function of Drosophila Keap1 xenobiotic response factor in nuclear architecture.

Background: The Keap1-Nrf2 pathway serves as a central regulator that mediates transcriptional responses to xenobiotic and oxidative stimuli. Recent studies have shown that Keap1 and Nrf2 can regulate transcripts beyond antioxidant and detoxifying genes, yet the underlying mechanisms remain unclear. Our research has uncovered that Drosophila Keap1 (dKeap1) and Nrf2 (CncC) proteins can control high-order chromatin structure, including heterochromatin.

Dog Life Spans and the Evolution of Aging.

AbstractThe basic tenets of the evolutionary theories of senescence are well supported. However, there has been little progress in determining the relative influences of mutation accumulation and life history optimization. The causes of the well-established inverse relationship between life span and body size across dog breeds are used here to test these two classes of theories.

Discovery of tumor-specific irreversible inhibitors of stearoyl CoA desaturase.

A hallmark of targeted cancer therapies is selective toxicity among cancer cell lines. We evaluated results from a viability screen of over 200,000 small molecules to identify two chemical series, oxalamides and benzothiazoles, that were selectively toxic at low nanomolar concentrations to the same 4 of 12 human lung cancer cell lines. Sensitive cell lines expressed cytochrome P450 (CYP) 4F11, which metabolized the compounds into irreversible inhibitors of stearoyl CoA desaturase (SCD).

High-dose oral medroxyprogesterone for inappropriate hypersexuality in elderly men with dementia: a case series.

Objective: To retrospectively examine the utility of high-dose oral medroxyprogesterone (MPA) for the treatment of inappropriate hypersexuality (IH) in elderly men with dementia.

Case Summary: Ten men aged 65 years or older (median 79.5 years, range 65-93 years) were identified from all admissions at a 170-bed tertiary referral psychiatric hospital between December 2005 and January 2011.

Opinions and experiences of Indiana pharmacists and student pharmacists: the need for addiction and substance abuse education in the United States.

Background: Substance abuse and addiction are growing public health problems. Pharmacists are potentially in a position to be of great assistance in ameliorating these threats yet might not be receiving the education and training to do so effectively.

Objective: To assess the relative perceived importance of substance abuse topics in pharmacy education among student pharmacists and pharmacy practitioners in the state of Indiana.