Keighley N. Reisenauer

Residual tumor burden and chemotherapy-resistance point to a need for drug leads active toward cancer stem cells. Just as natural products have led the way for current treatments, the potential for novel applications of these molecules remains high.

Infection with SARS-CoV-2 causes COVID-19 and has a well-established set of clinical symptoms. Olfactory and gustatory dysfunction are among the non-life threatening sequalae observed with both acute and chronic SARS-CoV-2 infection. This can lead to the loss of taste and smell and has been observed in large subsets of COVID-19 patients. Although non-life threatening, loss of taste and smell can contribute to decreased quality of life and prevent sufficient nutrient intake, which may negatively affect prognosis and recovery. Despite progress in the treatment of other symptoms caused by COVID-19, there are currently no standardized treatment protocols to mitigate loss of taste and smell caused by SARS-CoV-2 infection and most approaches thus far have evaluated sensory training and regimen-based treatment strategies independently. In this retrospective case series, we demonstrate the effectiveness of a comprehensive, combined treatment protocol for COVID-19-induced taste and smell dysfunction using olfactory and gustatory training in combination with vitamins and supplements, nasal irrigations, nerve stimulation exercises, and anti-inflammatory prophylaxis. Acutely infected patients with COVID-19-related loss of taste and smell were given a daily regimen of zinc, vitamin A, B-complex, vitamin D, and alpha lipoic acid in addition to saline nasal irrigation, fluticasone spray, nerve stimulation exercises, and repeated olfactory-gustatory training. Triamcinalone paste, theophylline, and prednisone were included daily with the observation of partial recovery. At two timepoints over approximately 20–37 days of treatment, taste and smell scores were quantified based on detection of agents included on each sensory training panel. Following this novel and comprehensive “Training ‘N’ Treatment” (TNT) protocol, every patient exhibited a complete recovery of taste and smell. Given the potential to provide relief to the many people with olfactory and gustatory dysfunction following SARS-CoV-2 infection, the effectiveness of this protocol warrants validation in a larger study.

The epithelial–mesenchymal transition (EMT) imparts properties of cancer stem-like cells, including resistance to frequently used chemotherapies, necessitating the identification of molecules that induce cell death specifically in stem-like cells with EMT properties. Herein, we demonstrate that breast cancer cells enriched for EMT features are more sensitive to cytotoxicity induced by ophiobolin A (OpA), a sesterterpenoid natural product. Using a model of experimentally induced EMT in human mammary epithelial (HMLE) cells, we show that EMT is both necessary and sufficient for OpA sensitivity. Moreover prolonged, sub-cytotoxic exposure to OpA is sufficient to suppress EMT-imparted CSC features including sphere formation and resistance to doxorubicin. In vivo growth of CSC-rich mammary cell tumors, is suppressed by OpA treatment. These data identify a driver of EMT-driven cytotoxicity with significant potential for use either in combination with standard chemotherapy or for tumors enriched for EMT features.

BackgroundGenetics literacy is crucial for making informed personal decisions. With rapid advances in genetic technology, a foundational understanding of genetics is now more important than ever for meaningful engagement with questions surrounding health, privacy, and policy. However, genetic content engagement barriers, including geographic unavailability, lack of prior education, and misleading media narratives, can make it difficult to reach diverse populations. Furthermore, with growing mistrust in science and genetic information, interventions to improve genetics literacy, particularly to those beyond a K – 12 classroom, require an approach centered on building science trust and self-efficacy. ResultsFor the meta-analysis, we found genetics content in 88 of the 691 museums queried, typically in science (n=37) and natural history (n=25) exhibits. While genetics content was present in 42 states, there were large portions of the country that were more than 150 miles away from any museum featuring genetics. We found a high concentration of genetics content in sponsored exhibits and a low concentration of content within children’s museums, reinforcing narratives of genetic technology as product and genetics as difficult, respectively. In framing devices, museums fell into one of three categories. Museums with the meta-narrative “Genetics is Fun” focused on interactivity and volunteer facilitation, and emphasized specific inherited traits and genetics tools and technology. Museums highlighting the meta-narrative “Genetics is Relevant” highlighted DNA basics and health testing. Finally, museums with the meta-narrative “Genetics is Discovery” featured heavy use of fishbowl-style genetics labs, highly visible museum collections, and an emphasis on visitor participation in science research. ConclusionWhile each of these meta-narratives leads to high engagement with genetics topics, they also all lead to construction of different personal identities around these topics. For example, watching a diverse set of scientists work in a fishbowl lab broadens definitions of who can be a scientist, but active participation in a genetics experiment through volunteer facilitation builds science self-efficacy. Furthermore, narratives focusing on technological breakthroughs alone may inadvertently send a message that genetics is complex and impersonal. Exhibit creators should consider the design ramifications of each of these choices when creating an impactful genetics exhibit.

Pharmacophore-directed retrosynthesis applied to ophiobolin A led to bicyclic derivatives that were synthesized and display anticancer activity. Key features of the ultimate defensive synthetic strategy include a Michael addition/facially selective protonation sequence to set the critical C6 stereocenter and a ring-closing metathesis to form the cyclooctene. Cytotoxicity assays toward a breast cancer cell line (MDA-MB-231) confirm the anticipated importance of structural complexity for selectivity (vs MCF10A cells) while C3 variations modulate stability.

The epithelial-mesenchymal transition (EMT) imparts properties of cancer stem-like cells, including resistance to frequently used chemotherapy, necessitating the identification of molecules that induce cell death specifically in stem-like cells with EMT properties. Herein, we demonstrate that breast cancer cells enriched for EMT features are more sensitive to cytotoxicity induced by ophiobolin A (OpA), a sesterterpenoid natural product. Using a model of experimentally induced EMT in human mammary epithelial (HMLE) cells, we show that EMT is both necessary and sufficient for OpA sensitivity. Moreover, prolonged, sub-cytotoxic exposure to OpA is sufficient to reduce migration, sphere formation, and resistance to doxorubicin. OpA is well-tolerated in mice and treatment with OpA alone reduces tumor burden. These data identify a driver of EMT-driven cytotoxicity with significant potential for use either in combination with standard chemotherapy or for tumors enriched for EMT features.

The epithelial-mesenchymal transition (EMT) enables the dissociation of cancer cells from the primary tumor by facilitating tolerance to lack of cell-adhesion, decreasing cellular division and increasing motility of individual cells, which leads to an invasive phenotype that links EMT to metastasis. Furthermore, EMT results in the acquisition of stem-cell markers and an increased ability to initiate tumor growth, supporting the concept that EMT may contribute to the development of a small, persistent sub-population of the tumor called cancer stem cells (CSCs). Cells that have undergone EMT have characteristically suppressed cell cycles, making them resistant to commonly used chemotherapies that target DNA replication or microtubule dynamics, processes essential to replicating cells. Nonspecific treatments can also rely on inducing apoptotic cell death; however, recent debates challenge the efficacy of apoptosis in solid tumors, citing high rates of acquired resistance. Utilizing a compound that induces alternative cell death, namely paraptosis, becomes attractive when these other treatments fail. Relying on an activated gene expression program, paraptosis results in the swelling of the mitochondria and endoplasmic reticulum and Apaf-1-independent alternative caspase-9 activity. Treating with paraptosis-inducing compounds such as Ophiobolin A (OpA) specifically targets otherwise-insensitive CSC and EMT cells to re-sensitize bulk tumor populations to chemotherapies. We describe EMT as a key driver of enhanced sensitivity to paraptosis-induced cell death following short-term treatment with OpA or other paraptosis-inducing compounds. Further, paraptosis selectively eliminates the CSC sub-population by reducing stem cell activity and highlights the potential of this pathway in breast cancer treatment. Citation Format: Reisenauer K, Tao Y, Ingros A, Philip T, Evidente A, Kornienko A, Romo D, Taube J. Epithelial-mesenchymal transition sensitizes breast cancer cells to paraptosis-mediated cell death via the fungus-derived sesterpenoid, Ophiobolin A [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-07-10.

The hypercalins are dearomatized acylphloroglucinols with a pendant complex cyclopentane ring that exhibit activity against several cancer cell lines. We report the first total synthesis of (+)‐hypercalin C employing a convergent strategy that enabled the dissection of the essential structural features required for the observed anticancer activity. A strategic disconnection involving an unusual C –C Suzuki–Miyaura coupling with an α‐bromo enolether also revealed an unexpected C−H activation. This strategy targeted designed analogues along the synthetic route to address particular biological questions. These results support the hypothesis that hypercalin C may act as a proton shuttle with the dearomatized acylphloroglucinol moiety being essential for this activity.

The H3K27me3-demethylase KDM6A is suppressed in breast cancer stem-like cells, and enables the resolution of bivalency during the mesenchymal-epithelial transition The H3K27me3-demethylase KDM6A is suppressed in breast cancer stem-like cells, and enables the resolution of bivalency during the mesenchymal-epithelial transition