US FDA public meeting: identification of concepts and terminology for multicomponent biomarkers.

The US FDA convened a virtual public workshop with the goals of obtaining feedback on the terminology needed for effective communication of multicomponent biomarkers and discussing the diverse use of biomarkers observed across the FDA and identifying common issues. The workshop included keynote and background presentations addressing the stated goals, followed by a series of case studies highlighting FDA-wide and external experience regarding the use of multicomponent biomarkers, which provided context for panel discussions focused on common themes, challenges and preferred terminology. The final panel discussion integrated the main concepts from the keynote, background presentations and case studies, laying a preliminary foundation to build consensus around the use and terminology of multicomponent biomarkers.

Establishing a Public Resource for Acceptable Surrogate Endpoints to Support FDA Marketing Applications.

Following a comprehensive and coordinated effort between CBER and CDER, FDA established a table of acceptable surrogate endpoints (SEs) to support drug marketing applications. The publicly accessible SE Table was first published in 2018 as a response to the 21st Century Cures Act legislation and is updated every 6 months to reflect current FDA thinking. The criteria for the table headings and content were chosen to foster succinctness and consistency, while reflecting the degree of scientific understanding for each listed SE.

Hsp90 Inhibition Results in Glucocorticoid Receptor Degradation in Association with Increased Sensitivity to Paclitaxel in Triple-Negative Breast Cancer.

Targetable molecular drivers for triple-negative breast cancer (TNBC) have been difficult to identify; therefore, standard treatment remains limited to conventional chemotherapy. Recently, new-generation small-molecule Hsp90 inhibitors (e.g.

Serum- and glucocorticoid-induced protein kinase 1 (SGK1) is regulated by store-operated Ca2+ entry and mediates cytoprotection against necrotic cell death.

Serum and glucocorticoid-regulated kinase 1 (SGK1) encodes a phosphatidylinositol 3-kinase-dependent serine/threonine kinase that is rapidly induced in response to cellular stressors and is an important cell survival signal. Previous studies have suggested that an increase in cytoplasmic Ca(2+) concentration ([Ca(2+)]c) is required for increased SGK1 expression, but the subcellular source of Ca(2+) regulating SGK1 transcription remains uncertain. Activation of endoplasmic reticulum stress (ERS) with thapsigargin (TG) increased SGK1 mRNA and protein expression in MDA-MB-231 cells.

Keap1-nrf2 signaling: a target for cancer prevention by sulforaphane.

Sulforaphane is a promising agent under preclinical evaluation in many models of disease prevention. This bioactive phytochemical affects many molecular targets in cellular and animal models; however, amongst the most sensitive is Keap1, a key sensor for the adaptive stress response system regulated through the transcription factor Nrf2. Keap1 is a sulfhydryl-rich protein that represses Nrf2 signaling by facilitating the polyubiquitination of Nrf2, thereby enabling its subsequent proteasomal degradation.

Transcriptomic and proteomic profiling of KEAP1 disrupted and sulforaphane-treated human breast epithelial cells reveals common expression profiles.

Sulforaphane (SFN), an isothiocyanate found in cruciferous vegetables, is a potent inhibitor of experimental mammary carcinogenesis and may be an effective, safe chemopreventive agent for use in humans. SFN acts in part on the Keap1/Nrf2 pathway to regulate a battery of cytoprotective genes. In this study, transcriptomic and proteomic changes in the estrogen receptor negative, non-tumorigenic human breast epithelial MCF10A cell line were analyzed following SFN treatment or KEAP1 knockdown with siRNA using microarray and stable isotopic labeling with amino acids in culture (SILAC), respectively.

Serotonin induces pulmonary artery smooth muscle cell migration.

The chronic phase of pulmonary arterial hypertension (PAH) is associated with vascular remodeling, especially thickening of the smooth muscle layer of large pulmonary arteries and muscularization of small pulmonary vessels, which normally have no associated smooth muscle. Serotonin (5-hydroxytryptamine, 5-HT) has been shown to induce proliferation and hypertrophy of pulmonary artery smooth muscle cells (PASMC), and may be important for in vivo pulmonary vascular remodeling. Here, we show that 5-HT stimulates migration of pulmonary artery PASMC.

Modulation of human GABAA and glycine receptor currents by menthol and related monoterpenoids.

Effects of common monoterpenoid alcohols and ketones were investigated on recombinant human gamma-aminobutyric acid A (GABAA; alpha1beta2gamma2s) and glycine (alpha1 homomers) receptors expressed in Xenopus oocytes. GABA currents were enhanced by coapplications of 10-300 microM: (+)-menthol>(-)-menthol>(-)-borneol>>(-)-menthone=camphor enantiomers>carvone enantiomers, with menthol acting stereoselectively. By contrast, thujone diastereomers inhibited GABAA receptor currents while glycine currents were only markedly potentiated by menthol.