Over 50,000 patients are diagnosed with head and neck cancers (HNC) in the United States each year and about half a million worldwide. Current treatment of HNC utilizes a multidisciplinary approach, ...radiotherapy alone or in combination with chemotherapy and surgery. The major drawbacks of radiotherapy treatment of HNC is radiation exposure of non-malignant tissue (i.e. salivary glands). The majority of HNC patients undergoing radiotherapy treatment suffer from chronic salivary dysfunction. Loss of saliva is associated with a multitude of complications (i.e. dental decay, dysphagia, oral infections, etc.), all of which contribute to deteriorating quality of life in HNC populations. Currently, there is no definite treatment for radiation-induced salivary gland dysfunction and available palliative care therapies are short-term and fail to improve quality of life. Stem cell-based therapies are a promising avenue for the treatment of salivary gland hypofunction and existence of salivary stem cell populations has been reported following radiation treatment. However, the effect of radiation on these putative populations, and whether they can be stimulated to regenerate and restore saliva production in the damaged salivary glands is unknown. Thus, understanding the intracellular effect of radiation on the salivary stem cell populations and their response upon radiation injury will facilitate development of novel therapies for the treatment of radiation-induced salivary gland dysfunction. Using a 3-dimensional suspension cell culture, we show that stem/progenitor cells derived from irradiated salivary glands have a defect in cell self-renewal and differentiation capacity, and our data indicates the role of aPKCζ in mediating these molecular events. We propose that utilization of the suspension cell culture assay to elucidate the upstream and downstream effects of aPKCζ will provide mechanistic insights that govern the non-responsive phenotype in the salivary stem/progenitor populations following radiation injury.
This paper describes a joint experiment–theory investigation of the formation and cyclization of 2′-alkynylacetophenone oxime radical cations using photoinduced electron transfer (PET) with DCA as ...the photosensitizer. Using a combination of experimental 1H and 13C nuclear magnetic resonance (NMR) spectra, high-resolution mass spectrometry, and calculated NMR chemical shifts, we identified the products to be isoindole N-oxides. The reaction was found to be stereoselective; only one of the two possible stereoisomers is formed under these conditions. A detailed computational investigation of the cyclization reaction mechanism suggests facile C–N bond formation in the radical cation leading to a 5-exo intermediate. Back-electron transfer from the DCA radical anion followed by barrierless intramolecular proton transfer leads to the final product. We argue that the final proton transfer step in the mechanism is responsible for the stereoselectivity observed in experiment. As a whole, this work provides new insights into the formation of complex heterocycles through oxime and oxime ether radical cation intermediates produced via PET. Moreover, it represents the first reported formation of isoindole N-oxides.
