Phase II trial of the PI3 kinase inhibitor buparlisib (BKM-120) with or without enzalutamide in men with metastatic castration resistant prostate cancer.

Background: Phosphatidylinositol-3-kinase (PI3K) and androgen receptor pathway activation is common in metastatic castration resistant prostate cancer (mCRPC). Buparlisib is an oral, pan-class I PI3 kinase inhibitor.

Methods: This was a multisite single arm phase II trial of buparlisib 100 mg ± enzalutamide daily in men with mCRPC whose disease progressed on or who were not candidates for docetaxel.

Development of a Novel c-MET-Based CTC Detection Platform.

Unlabelled: Amplification of the MET oncogene is associated with poor prognosis, metastatic dissemination, and drug resistance in many malignancies. We developed a method to capture and characterize circulating tumor cells (CTC) expressing c-MET using a ferromagnetic antibody. Immunofluorescence was used to characterize cells for c-MET, DAPI, and pan-CK, excluding CD45(+) leukocytes.

Cathepsin B contributes to Na+ hyperabsorption in cystic fibrosis airway epithelial cultures.

In cystic fibrosis (CF) lung disease, the absence of functional CF transmembrane conductance regulator results in Cl(-)/HCO3 (-) hyposecretion and triggers Na(+) hyperabsorption through the epithelial Na(+) channel (ENaC), which contribute to reduced airway surface liquid (ASL) pH and volume. Prostasin, a membrane-anchored serine protease with trypsin-like substrate specificity has previously been shown to activate ENaC in CF airways. However, prostasin is typically inactive below pH 7.

Identification of the SPLUNC1 ENaC-inhibitory domain yields novel strategies to treat sodium hyperabsorption in cystic fibrosis airway epithelial cultures.

The epithelial sodium channel (ENaC) is responsible for Na(+) and fluid absorption across colon, kidney, and airway epithelia. Short palate lung and nasal epithelial clone 1 (SPLUNC1) is a secreted, innate defense protein and an autocrine inhibitor of ENaC that is highly expressed in airway epithelia. While SPLUNC1 has a bactericidal permeability-increasing protein (BPI)-type structure, its NH2-terminal region lacks structure.

Molecular basis for pH-dependent mucosal dehydration in cystic fibrosis airways.

The ability to maintain proper airway surface liquid (ASL) volume homeostasis is vital for mucus hydration and clearance, which are essential aspects of the mammalian lung's innate defense system. In cystic fibrosis (CF), one of the most common life-threatening genetic disorders, ASL dehydration leads to mucus accumulation and chronic infection. In normal airways, the secreted protein short palate lung and nasal epithelial clone 1 (SPLUNC1) effectively inhibits epithelial Na(+) channel (ENaC)-dependent Na(+) absorption and preserves ASL volume.

Does epithelial sodium channel hyperactivity contribute to cystic fibrosis lung disease?

  Airway epithelia absorb Na+ through the epithelial Na+ channel (ENaC) and secrete Cl- through the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. This balance maintains sufficient airway surface liquid hydration to permit efficient mucus clearance, which is needed to maintain sterility of the lung. Cystic fibrosis (CF) is a common autosomal recessive inherited disease caused by mutations in the CFTR gene that lead to the reduction or elimination of the CFTR protein.

Identification of SPLUNC1's ENaC-inhibitory domain yields novel strategies to treat sodium hyperabsorption in cystic fibrosis airways.

The epithelial sodium channel (ENaC) is responsible for Na+ and fluid absorption across colon, kidney, and airway epithelia. We have previously identified SPLUNC1 as an autocrine inhibitor of ENaC. We have now located the ENaC inhibitory domain of SPLUNC1 to SPLUNC1's N terminus, and a peptide corresponding to this domain, G22-A39, inhibited ENaC activity to a similar degree as full-length SPLUNC1 (∼2.

NMR solution structure and DNA-binding model of the DNA-binding domain of competence protein A.

Competence protein A (ComA) is a response regulator protein involved in the development of genetic competence in the Gram-positive spore-forming bacterium Bacillus subtilis, as well as the regulation of the production of degradative enzymes and antibiotic synthesis. ComA belongs to the NarL family of proteins, which are characterized by a C-terminal transcriptional activator domain that consists of a bundle of four helices, where the second and third helices (alpha 8 and alpha 9) form a helix-turn-helix DNA-binding domain. Using NMR spectroscopy, the high-resolution 3D solution structure of the C-terminal DNA-binding domain of ComA (ComAC) has been determined.

Structural characterization of the conformational change in calbindin-D28k upon calcium binding using differential surface modification analyzed by mass spectrometry.

Calbindin-D28k is a calcium binding protein with six EF hand domains. Calbindin-D28k is unique in that it functions as both a calcium buffer and a sensor protein. It is found in many tissues, including brain, pancreas, kidney, and intestine, playing important roles in each.