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The current state of obscenity law is muddled, to say the least. The test itself is clear, laid out in the seminal case Miller v. California. However, the vagueness of the prongs of this test has resulted in varied and confusing application that leaves the actual standard for obscenity difficult to discern in practice. And unlike the many other types of expression that have been found by the Supreme Court to fall under the First Amendment, obscenity remains just taboo enough to stay beyond the scope of free speech protection. While Americans have proven themselves willing to tolerate greater and greater amounts of sexual content in movies and television, it remains the law of the land that there is a "too much," and bumping up against the line of "too much" can have serious legal repercussions such as seizure of property, fines, and even imprisonment. American society has become increasingly sexually liberated over the last century, but there is a growing resistance to that trend. The continued availability of the Miller test could lead to a renewed era of obscenity prosecution and sexual repression. The inherent subjectivity of the "artistic merit" prong in particular allows art to be censored by those who do not understand it based on personal values rather than an objective legal standard. In this Note, I discuss the history and development of current obscenity doctrine and criticize the Court's current test primarily through the lens of cinema, focusing on the prong that measures the "artistic merit" of the allegedly obscene work. My discussion contains both actual, historical application of the Miller test, as well as its theoretical application to films that blur the line between obscenity and non-obscenity, to highlight the vagueness and inconsistency of the Miller standard. Ultimately, I hope to highlight that while "obscene" works can pose some additional problems for society not typically presented by other types of media, the current test is simply untenable, and neither properly remedies those problems nor ensures that only such problematic works will be censored. [ABSTRACT FROM AUTHOR]

L6398 --> 505.18 --> Within head and neck squamous cell carcinomas (HNSCCs), oral and oropharyngeal squamous cell carcinomas (SCCs) affect ~34,000 people in the US each year. Patients face a 50% 5‐year survival rate and overall decline in quality of life due to morbidities of current treatments. Novel targeted therapies are needed for SCCs to prolong survival and decrease off‐target effects of treatment. Due to the oral localization of SCCs, bitter taste receptor (T2R) GPCRs have sparked interest as potential therapeutic targets. We showed that upregulated T2R expression may be associated with higher overall survival in HNSCC and may serve as a predictive biomarker. T2R activation by bitter agonists induces apoptosis in HNSCC cells. Here, we show that bitter local anesthetics have apoptotic effects in HNSCC cells: SCC47, SCC4, and FaDu. Lidocaine (10 mM; a concentration within the clinically used range) activates T2R calcium responses that are inhibited by pertussis toxin, an inhibitor of Gi/o– coupled GPCRs, and by suramin, an inhibitor of Ga. This was distinct from the structurally‐related T2R agonist denatonium, which activates calcium responses inhibited by Gq inhibitor YM‐254890 but not pertussis toxin. Lidocaine induces initial calcium release from intracellular reservoirs sustained by calcium influx. HNSCC cells have a larger calcium response with lidocaine than with T2R agonists denatonium, thujone, procaine, and caffeine. Lidocaine exhausts cells and inhibits subsequent secondary purinergic calcium responses. Using biosensors localized to the ER or mitochondria, we found that ER calcium is depleted upon lidocaine stimulation while mitochondrial calcium is increased. Using lysosomal K+/H+ proton gradient inhibitor nigericin, we observed that lidocaine also causes calcium depletion of lysosomal stores. Consistent with ER depletion, lidocaine stimulates ER stress, upregulating XBP‐1. Lidocaine reduces NADH metabolism via XTT assay, indicative of reduced cellular health. Lidocaine also reduces mitochondrial potential as measured by JC‐1 dye and simultaneously promotes apoptosis, with cleavage of both caspase‐3 and ‐7, measured by Western and live cell imaging. Interestingly, lidocaine upregulates both cleaved and full‐length caspase‐3 and ‐7 proteins, even in the presence of cycloheximide. The mRNA products of both caspase proteins are not upregulated. This suggests a possible inhibition of protein degradation involved in lidocaine‐induced apoptosis. Induction of pro‐apoptotic protein BAX also occurs upon lidocaine stimulation. Lidocaine also induced cell death in Matrigel culture. Together, our data show that lidocaine should be viewed as more than a local anesthetic within HNSCC surgical settings. Lidocaine or other T2R agonists may aid in eradication of residual cancer cells and extend time between initial surgery and reoccurrence/metastasis as an alternative or complementary therapy. With their promising effects on oral and oropharyngeal SCC cells and accessibility of the oral cavity to topically applied lidocaine gels, further work is warranted to understand the effects of bitter local anesthetics and T2R signaling in HNSCC and normal surrounding epithelia. [ABSTRACT FROM AUTHOR]

T2R bitter taste receptors in airway motile cilia increase ciliary beat frequency (CBF) and nitric oxide (NO) production. Polymorphisms in some T2Rs are linked to disease outcomes in chronic rhinosinusitis (CRS) and cystic fibrosis (CF). We examined the expression of cilia T2Rs during the differentiation of human nasal epithelial cells grown at air–liquid interface (ALI). The T2R expression increased with differentiation but did not vary between CF and non-CF cultures. Treatment with Pseudomonas aeruginosa flagellin decreased the expression of diphenhydramine-responsive T2R14 and 40, among others. Diphenhydramine increased both NO production, measured by fluorescent dye DAF-FM, and CBF, measured via high-speed imaging. Increases in CBF were disrupted after flagellin treatment. Diphenhydramine impaired the growth of lab and clinical strains of P. aeruginosa, a major pathogen in CF and CF-related CRS. Diphenhydramine impaired biofilm formation of P. aeruginosa, measured via crystal violet staining, as well as the surface attachment of P. aeruginosa to CF airway epithelial cells, measured using colony-forming unit counting. Because the T2R agonist diphenhydramine increases NO production and CBF while also decreasing bacterial growth and biofilm production, diphenhydramine-derived compounds may have potential clinical usefulness in CF-related CRS as a topical therapy. However, utilizing T2R agonists as therapeutics within the context of P. aeruginosa infection may require co-treatment with anti-inflammatories to enhance T2R expression. [ABSTRACT FROM AUTHOR]