Frontal and anterior temporal hypometabolism post chemoradiation in head and neck cancer: A real-world PET study.

BACKGROUND AND PURPOSE: Adverse neurological effects after cancer therapy are common, but biomarkers to diagnose, monitor, or risk stratify patients are still not validated or used clinically. An accessible imaging method, such as fluorodeoxyglucose positron emission tomography (FDG PET) of the brain, could meet this gap and serve as a biomarker for functional brain changes. We utilized FDG PET to evaluate which brain regions are most susceptible to altered glucose metabolism after chemoradiation in patients with head and neck cancer (HNCa). METHODS: Real-world FDG PET images were acquired as standard of care before and after chemoradiation for HNCa in 68 patients. Linear mixed-effects voxelwise models assessed changes after chemoradiation in cerebral glucose metabolism quantified with standardized uptake value ratio (SUVR), covarying for follow-up time and patient demographics. RESULTS: Voxelwise analysis revealed two large clusters of decreased glucose metabolism in the medial frontal and polar temporal cortices following chemoradiation, with decreases of approximately 5% SUVR after therapy. CONCLUSIONS: These findings provide evidence that standard chemoradiation for HNCa can lead to decreased neuronal glucose metabolism, contributing to literature emphasizing the vulnerability of the frontal and anterior temporal lobes, especially in HNCa, where these areas may be particularly vulnerable to indirect radiation-induced injury. FDG PET shows promise as a sensitive biomarker for assessing these changes.

Development of an anti-Pseudomonas aeruginosa therapeutic monoclonal antibody WVDC-5244.

The rise of antimicrobial-resistant bacterial infections is a crucial health concern in the 21st century. In particular, antibiotic-resistant Pseudomonas aeruginosa causes difficult-to-treat infections associated with high morbidity and mortality. Unfortunately, the number of effective therapeutic interventions against antimicrobial-resistant P. aeruginosa infections continues to decline. Therefore, discovery and development of alternative treatments are necessary. Here, we present pre-clinical efficacy studies on an anti-P. aeruginosa therapeutic monoclonal antibody. Using hybridoma technology, we generated a monoclonal antibody and characterized its binding to P. aeruginosa in vitro using ELISA and fluorescence correlation spectroscopy. We also characterized its function in vitro and in vivo against P. aeruginosa. The anti-P. aeruginosa antibody (WVDC-5244) bound P. aeruginosa clinical strains of various serotypes in vitro, even in the presence of alginate exopolysaccharide. In addition, WVDC-5244 induced opsonophagocytic killing of P. aeruginosa in vitro in J774.1 murine macrophage, and complement-mediated killing. In a mouse model of acute pneumonia, prophylactic administration of WVDC-5244 resulted in an improvement of clinical disease manifestations and reduction of P. aeruginosa burden in the respiratory tract compared to the control groups. This study provides promising pre-clinical efficacy data on a new monoclonal antibody with therapeutic potential for P. aeruginosa infections.

Identification of 4-(2-(4-amino-1,2,5-oxadiazol-3-yl)-1-ethyl-7-{[(3S)-3-piperidinylmethyl]oxy}-1H-imidazo[4,5-c]pyridin-4-yl)-2-methyl-3-butyn-2-ol (GSK690693), a novel inhibitor of AKT kinase.

Overexpression of AKT has an antiapoptotic effect in many cell types, and expression of dominant negative AKT blocks the ability of a variety of growth factors to promote survival. Therefore, inhibitors of AKT kinase activity might be useful as monotherapy for the treatment of tumors with activated AKT. Herein, we describe our lead optimization studies culminating in the discovery of compound 3g (GSK690693). Compound 3g is a novel ATP competitive, pan-AKT kinase inhibitor with IC 50 values of 2, 13, and 9 nM against AKT1, 2, and 3, respectively. An X-ray cocrystal structure was solved with 3g and the kinase domain of AKT2, confirming that 3g bound in the ATP binding pocket. Compound 3g potently inhibits intracellular AKT activity as measured by the inhibition of the phosphorylation levels of GSK3beta. Intraperitoneal administration of 3g in immunocompromised mice results in the inhibition of GSK3beta phosphorylation and tumor growth in human breast carcinoma (BT474) xenografts.

New benzylidenethiazolidinediones as antibacterial agents.

A novel benzylidenethiazolidinedione has been discovered with antimicrobial activity. Here, we present the results of a structure-activity study on this compound with respect to its antimicrobial activity.

A practical enantioselective total synthesis of the bengamides B, E, and Z.

[reaction: see text] A practical total synthesis of Bengamides B, E, and Z from a common polyol intermediate is described. Consecutive aldol condensations afford a protected polyol thioester side chain suitable for coupling to the Bengamides. A novel chiral phase transfer catalyzed enantioselective alkylation affords the more highly functionalized amino caprolactams required for Bengamides B and Z. Use of the 2-naphthylmethyl ether protecting group, compatible with the boron Lewis acids required for enantioselective aldol condensation, allows direct access to Bengamide B.