When Hexokinase Gets that NAG-ing Feeling….
Ontology highlight
ABSTRACT:
SUBMITTER: O'Sullivan D
PROVIDER: S-EPMC5572107 | biostudies-other | 2016 Aug
REPOSITORIES: biostudies-other
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Project description:BackgroundPrevious studies have established that sex workers experience discrimination and stigma within healthcare settings, limiting their access and receipt of culturally safe care. These barriers impact sex workers' ability and desire to routinely engage with the healthcare system. Community empowerment interventions that are culturally safe offer an effective strategy to improve access to services and health outcomes for sex workers.ObjectivesThis project was designed to inform the development of community empowerment interventions for sex workers by understanding their self-management, health promotion, and harm reduction needs.MethodsIn-depth interviews (N = 21) were conducted with sex workers in Chicago. Transcripts of individual interviews were analyzed in Dedoose using rapid content analysis.ResultsParticipants had a mean age of 32.7 years; 45% identified as White, 20% as Black, 15% as Latinx, and 20% as multiple races; 80% identified as Queer. A total of 52% of participants identified as cisgender women, 33% as transgender or gender fluid, 10% as cisgender men, and 5% declined to answer. Themes of self-management practices, stigmatizing and culturally unsafe experiences with healthcare providers, and the prohibitive cost of healthcare emerged as consistent barriers to routinely accessing healthcare. Despite identifying patient-centered care as a desired healthcare model, many participants did not report receiving care that was respectful or culturally responsive. Themes also included developing strategies to identify sex worker-safe care providers, creating false self-narratives and health histories in order to safely access care, and creating self-care routines that serve as alternatives to primary care.ConclusionOur findings demonstrate how patient-centered care for sex-workers in Chicago might include holistic wellness exercises, accessible pay scales for services, and destigmatizing healthcare praxis. Focus on culturally safe healthcare provision presents needs beyond individualized, or even community-level, interventions. Ongoing provider training and inbuilt, systemic responsivity to patient needs and contexts is crucial to patient-centered care.
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Project description:Many philosophers and psychologists have made claims about what is felt in an experience of beauty. Here, we test how well these claims match the feelings that people report while looking at an image, or listening to music, or recalling a personal experience of beauty. We conducted ten experiments (total n = 851) spanning three nations (US, UK, and India). Across nations and modalities, top-rated beauty experiences are strongly characterized by six dimensions: intense pleasure, an impression of universality, the wish to continue the experience, exceeding expectation, perceived harmony in variety, and meaningfulness. Other frequently proposed beauty characteristics - like surprise, desire to understand, and mind wandering - are uncorrelated with feeling beauty. A typical remembered beautiful experience was active and social like a family holiday - hardly ever mentioning beauty - and only rarely mentioned art, unlike the academic emphasis, in aesthetics, on solitary viewing of art. Our survey aligns well with Kant and the psychological theories that emphasize pleasure, and reject theories that emphasize information seeking.
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Project description:BackgroundPrecision medicine therapies require identification of unique molecular cancer characteristics. Hexokinase (HK) activity has been proposed as a therapeutic target; however, different hexokinase isoforms have not been well characterized as alternative targets. While HK2 is highly expressed in the majority of cancers, cancer subtypes with differential HK1 and HK2 expression have not been characterized for their sensitivities to HK2 silencing.MethodsHK1 and HK2 expression in the Cancer Cell Line Encyclopedia dataset was analyzed. A doxycycline-inducible shRNA silencing system was used to examine the effect of HK2 knockdown in cultured cells and in xenograft models of HK1-HK2+ and HK1+HK2+ cancers. Glucose consumption and lactate production rates were measured to monitor HK activity in cell culture, and 18F-FDG PET/CT was used to monitor HK activity in xenograft tumors. A high-throughput screen was performed to search for synthetically lethal compounds in combination with HK2 inhibition in HK1-HK2+ liver cancer cells, and a combination therapy for liver cancers with this phenotype was developed. A metabolomic analysis was performed to examine changes in cellular energy levels and key metabolites in HK1-HK2+ cells treated with this combination therapy. The CRISPR Cas9 method was used to establish isogenic HK1+HK2+ and HK1-HK2+ cell lines to evaluate HK1-HK2+ cancer cell sensitivity to the combination therapy.ResultsMost tumors express both HK1 and HK2, and subsets of cancers from a wide variety of tissues of origin express only HK2. Unlike HK1+HK2+ cancers, HK1-HK2+ cancers are sensitive to HK2 silencing-induced cytostasis. Synthetic lethality was achieved in HK1-HK2+ liver cancer cells, by the combination of DPI, a mitochondrial complex I inhibitor, and HK2 inhibition, in HK1-HK2+ liver cancer cells. Perhexiline, a fatty acid oxidation inhibitor, further sensitizes HK1-HK2+ liver cancer cells to the complex I/HK2-targeted therapeutic combination. Although HK1+HK2+ lung cancer H460 cells are resistant to this therapeutic combination, isogenic HK1KOHK2+ cells are sensitive to this therapy.ConclusionsThe HK1-HK2+ cancer subsets exist among a wide variety of cancer types. Selective inhibition of the HK1-HK2+ cancer cell-specific energy production pathways (HK2-driven glycolysis, oxidative phosphorylation and fatty acid oxidation), due to the unique presence of only the HK2 isoform, appears promising to treat HK1-HK2+ cancers. This therapeutic strategy will likely be tolerated by most normal tissues, where only HK1 is expressed.
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Project description:Parasites in the genus Plasmodium cause disease throughout the tropic and subtropical regions of the world. P. falciparum, one of the deadliest species of the parasite, relies on glycolysis for the generation of ATP while it inhabits the mammalian red blood cell. The first step in glycolysis is catalyzed by hexokinase (HK). While the 55.3-kDa P. falciparum HK (PfHK) shares several biochemical characteristics with mammalian HKs, including being inhibited by its products, it has limited amino acid identity (~26%) to the human HKs, suggesting that enzyme-specific therapeutics could be generated. To that end, interrogation of a selected small-molecule library of HK inhibitors has identified a class of PfHK inhibitors, isobenzothiazolinones, some of which have 50% inhibitory concentrations (IC50s) of <1 ?M. Inhibition was reversible by dilution but not by treatment with a reducing agent, suggesting that the basis for enzyme inactivation was not covalent association with the inhibitor. Lastly, six of these compounds and the related molecule ebselen inhibited P. falciparum growth in vitro (50% effective concentration [EC50] of ? 0.6 and <6.8 ?M). These findings suggest that the chemotypes identified here could represent leads for future development of therapeutics against P. falciparum.
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