A Multivalent Peptoid Conjugate Modulates Androgen Receptor Transcriptional Activity to Inhibit Therapy-resistant Prostate Cancer.

Prostate cancers adapt to androgen receptor (AR) pathway inhibitors and progress to castration resistance due to ongoing AR expression and function. To counter this, we developed a new approach to modulate the AR and inhibit castration-resistant prostate cancer (CRPC) using multivalent peptoid conjugates (MPC) that contain multiple copies of the AR-targeting ligand ethisterone attached to a peptidomimetic scaffold. Here, we investigated the antitumor effects of compound MPC309, a trivalent display of ethisterone conjugated to a peptoid oligomer backbone that binds to the AR with nanomolar affinity.

Inhibiting LXRα phosphorylation in hematopoietic cells reduces inflammation and attenuates atherosclerosis and obesity in mice.

Atherosclerosis and obesity share pathological features including inflammation mediated by innate and adaptive immune cells. LXRα plays a central role in the transcription of inflammatory and metabolic genes. LXRα is modulated by phosphorylation at serine 196 (LXRα pS196), however, the consequences of LXRα pS196 in hematopoietic cell precursors in atherosclerosis and obesity have not been investigated.

Dickkopf-1 Can Lead to Immune Evasion in Metastatic Castration-Resistant Prostate Cancer.

Purpose: Metastatic castration-resistant prostate cancer (mCRPC) with low androgen receptor (AR) and without neuroendocrine signaling, termed double-negative prostate cancer (DNPC), is increasingly prevalent in patients treated with AR signaling inhibitors and is in need of new biomarkers and therapeutic targets.

Methods: Candidate genes enriched in DNPC were determined using differential gene expression analysis of discovery and validation cohorts of mCRPC biopsies. Laboratory studies were carried out in human mCRPC organoid cultures, prostate cancer (PCa) cell lines, and mouse xenograft models.

Design of Peptoid-peptide Macrocycles to Inhibit the β-catenin TCF Interaction in Prostate Cancer.

New chemical inhibitors of protein-protein interactions are needed to propel advances in molecular pharmacology. Peptoids are peptidomimetic oligomers with the capability to inhibit protein-protein interactions by mimicking protein secondary structure motifs. Here we report the in silico design of a macrocycle primarily composed of peptoid subunits that targets the β-catenin:TCF interaction.

Revisiting the role of Wnt/β-catenin signaling in prostate cancer.

The androgen receptor (AR) is a widely accepted therapeutic target in prostate cancer and multiple studies indicate that the AR and Wnt/β-catenin pathways intersect. Recent genome-wide analysis of prostate cancer metastases illustrate the importance of the Wnt/β-catenin pathway in prostate cancer and compel us to reexamine the interaction of the AR and Wnt/β-catenin signaling pathways. This review includes newer areas of interest such as non-canonical Wnt signaling and the role of Wnts in prostate cancer stem cells.

RNA helicase A activity is inhibited by oncogenic transcription factor EWS-FLI1.

RNA helicases impact RNA structure and metabolism from transcription through translation, in part through protein interactions with transcription factors. However, there is limited knowledge on the role of transcription factor influence upon helicase activity. RNA helicase A (RHA) is a DExH-box RNA helicase that plays multiple roles in cellular biology, some functions requiring its activity as a helicase while others as a protein scaffold.

Manganese-induced oxidative DNA damage in neuronal SH-SY5Y cells: attenuation of thymine base lesions by glutathione and N-acetylcysteine.

Manganese (Mn) is an essential trace element required for normal function and development. However, exposure to this metal at elevated levels may cause manganism, a progressive neurodegenerative disorder with neurological symptoms similar to idiopathic Parkinson's disease (IPD). Elevated body burdens of Mn from exposure to parental nutrition, vapors in mines and smelters and welding fumes have been associated with neurological health concerns.

Institutional practices of withholding enteral feeding from intubated patients.

Objective: This study compared the practices of anesthesia, anesthesia critical care, surgical critical care, and medical critical care departments that have training programs for the length of time they withhold enteral feeding from intubated patients before seven scheduled procedures: 1) extubation; 2) tracheostomy; 3) abdominal surgery; 4) nonabdominal surgery; 5) magnetic resonance imaging or computerized tomography; or placing the patient in the 6) Trendelenberg or 7) prone position.

Design: One-time survey of 297 anesthesia and critical care training programs in the United States.

Measurements And Main Results: Eighty programs responded (27%).