Identification Of Novel Anti-Brain Tumor-Initiating Cell Compounds Using High-Throughput Screening

Glioblastoma multiforme is the most common malignant primary intracranial tumor in adults. Despite years of advances in basic science knowledge about this disease including but not limited to cellular hierarchy, genetics, and mechanisms of proliferation and spread, overall survival of patients has remained unmoved for the past fifteen years, and long-term survivors are nearly nonexistent. Barriers to improved treatment occur in the realms of engineering and drug discovery: creation of an efficient delivery vehicle and identification of novel, efficacious small molecule compounds are necessary to achieve survival benefit in this disease. In the following thesis, I describe efforts made by myself individually and alongside members of the laboratory of W Mark Saltzman, PhD, Goizueta Foundation Professor and Chairman of Biomedical Engineering, to test a novel, highly-penetrative polymeric nanocarrier platform for intracranial drug delivery and develop a high-throughput screen for small molecule compounds with efficacy against brain cancer stem cells. I show that the combination of the efficient delivery system and small molecule compounds with efficacy against brain cancer stem cells produces unprecedented gains in survival in a rat model of glioblastoma. Further, I describe the design and quality control methodology of the high-throughput small molecule screen and identify a large number of small molecule compounds with equal efficacy to first-generation anti-brain cancer stem cell drugs with fewer safety concerns. Together, the data underscore a) the promise of this efficient delivery vehicle to rapidly test the identified anti-brain cancer stem cell compounds and b) the potential for this combination to revolutionize glioblastoma therapy

Impacts of Scheduling Recess Before Lunch in Elementary Schools: A Case Study Approach of Plate Waste and Perceived Behaviors

Purpose/Objectives Recess Before Lunch (RBL) for elementary students is considered a best practice related to increased nutrient intakes at lunch, decreased afternoon behavioral issues, and increased afternoon learning efficiency; however, school characteristics, such as amount of time for lunch, offer vs. serve, and scheduling factors can influence implementation. A qualitative study to examine impacts of RBL on plate waste and school stakeholders’ perceptions of third grade students’ behaviors in three school districts in one Midwest state was conducted. The results were used to develop a guide that includes tools and best practices to assist schools in determination of recess scheduling. Methods Digital photography and weight-based assessment of plate waste by meal component were collected among third-graders in three geographically distinct, independent school districts with varying student enrollments. Data were collected on two occasions in fall when recess was scheduled after lunch and again in spring when recess was scheduled before lunch. Following completion of a short survey, interviews with multiple stakeholders at each school building were conducted in fall and spring to assess views of the benefits and challenges associated with changing to recess before lunch. Results Plate waste and fluid milk consumption varied between sites. Findings suggest other environmental influences affect food and milk consumption beyond scheduling of recess. Digital photography method of plate waste estimation was validated with comparisons to actual weights and measures. Application to Child Nutrition Professionals Findings from this study were utilized to develop a guide to assist decision makers considering moving recess before lunch. The guide includes tools and best practices to assist schools in the determination of making the change to recess before lunch. The guide is located on the USDA State Sharing Center webpage and available as a resource to all interested parties

Dose optimisation and scarce resource allocation: two sides of the same coin

Objective: A deep understanding of the relationship between a scarce drug's dose and clinical response is necessary to appropriately distribute a supply-constrained drug along these lines. Summary of key data: The vast majority of drug development and repurposing during the COVID-19 pandemic – an event that has made clear the ever-present scarcity in healthcare systems –has been ignorant of scarcity and dose optimisation's ability to help address it. Conclusions: Future pandemic clinical trials systems should obtain dose optimisation data, as these appear necessary to enable appropriate scarce resource allocation according to societal values

A Transcriptomic Signature of the Hypothalamic Response to Fasting and BDNF Deficiency in Prader-Willi Syndrome.

Transcriptional analysis of brain tissue from people with molecularly defined causes of obesity may highlight disease mechanisms and therapeutic targets. We performed RNA sequencing of hypothalamus from individuals with Prader-Willi syndrome (PWS), a genetic obesity syndrome characterized by severe hyperphagia. We found that upregulated genes overlap with the transcriptome of mouse Agrp neurons that signal hunger, while downregulated genes overlap with the expression profile of Pomc neurons activated by feeding. Downregulated genes are expressed mainly in neuronal cells and contribute to neurogenesis, neurotransmitter release, and synaptic plasticity, while upregulated, predominantly microglial genes are involved in inflammatory responses. This transcriptional signature may be mediated by reduced brain-derived neurotrophic factor expression. Additionally, we implicate disruption of alternative splicing as a potential molecular mechanism underlying neuronal dysfunction in PWS. Transcriptomic analysis of the human hypothalamus may identify neural mechanisms involved in energy homeostasis and potential therapeutic targets for weight loss

Adopting Weight-Based Dosing With Pharmacy-Level Stewardship Strategies Could Reduce Cancer Drug Spending By Millions

Immune checkpoint inhibitors, a class of drugs used in approximately forty unique cancer indications, are a sizable component of the economic burden of cancer care in the US. Instead of personalized weight-based dosing, immune checkpoint inhibitors are most commonly administered at one-size-fits-all flat doses that are higher than necessary for the vast majority of patients. We hypothesized that personalized weight-based dosing along with common stewardship efforts at the pharmacy level, such as dose rounding and vial sharing, would lead to reductions in immune checkpoint inhibitor use and lower spending. Using data from the Veterans Health Administration (VHA) and Medicare drug prices, we estimated reductions in immune checkpoint inhibitor use and spending that would be associated with pharmacy-level stewardship strategies, in a case-control simulation study of individual patient-level immune checkpoint inhibitor administration events. We identified baseline annual VHA spending for these drugs of approximately $537 million. Combining weight-based dosing, dose rounding, and pharmacy-level vial sharing would generate expected annual VHA health system savings of$74 million (13.7 percent). We conclude that adoption of pharmacologically justified immune checkpoint inhibitor stewardship measures would generate sizable reductions in spending for these drugs. Combining these operational innovations with value-based drug price negotiation enabled by recent policy changes may improve the long-term financial viability of cancer care in the US

Lorlatinib Exposed: A Far From Optimal Dose

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/172839/1/cpt2579_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/172839/2/cpt2579.pd

Impacts of Scheduling Recess Before Lunch in Elementary Schools: A Case Study Approach of Plate Waste and Perceived Behaviors

Purpose/Objectives Recess Before Lunch (RBL) for elementary students is considered a best practice related to increased nutrient intakes at lunch, decreased afternoon behavioral issues, and increased afternoon learning efficiency; however, school characteristics, such as amount of time for lunch, offer vs. serve, and scheduling factors can influence implementation. A qualitative study to examine impacts of RBL on plate waste and school stakeholders’ perceptions of third grade students’ behaviors in three school districts in one Midwest state was conducted. The results were used to develop a guide that includes tools and best practices to assist schools in determination of recess scheduling. Methods Digital photography and weight-based assessment of plate waste by meal component were collected among third-graders in three geographically distinct, independent school districts with varying student enrollments. Data were collected on two occasions in fall when recess was scheduled after lunch and again in spring when recess was scheduled before lunch. Following completion of a short survey, interviews with multiple stakeholders at each school building were conducted in fall and spring to assess views of the benefits and challenges associated with changing to recess before lunch. Results Plate waste and fluid milk consumption varied between sites. Findings suggest other environmental influences affect food and milk consumption beyond scheduling of recess. Digital photography method of plate waste estimation was validated with comparisons to actual weights and measures. Application to Child Nutrition Professionals Findings from this study were utilized to develop a guide to assist decision makers considering moving recess before lunch. The guide includes tools and best practices to assist schools in the determination of making the change to recess before lunch. The guide is located on the USDA State Sharing Center webpage and available as a resource to all interested parties.This article is published as Strohbehn , C.H., Strohbehn, G., Lanningham-Foster, L., Litchfield, R., Scheidel, C., & Delger, P. Impacts of Scheduling Recess Before Lunch in Elementary Schools: A Case Study Approach of Plate Waste and Perceived Behaviors. Journal of Child Nutrition and Management, 40(1). Posted with permission.</p

Targeted randomization dose optimization trials enable fractional dosing of scarce drugs.

Administering drug at a dose lower than that used in pivotal clinical trials, known as fractional dosing, can stretch scarce resources. Implementing fractional dosing with confidence requires understanding a drug's dose-response relationship. Clinical trials aimed at describing dose-response in scarce, efficacious drugs risk underdosing, leading dose-finding trials to not be pursued despite their obvious potential benefit. We developed a new set of response-adaptive randomized dose-finding trials and demonstrate, in a series of simulated trials across diverse dose-response curves, these designs' efficiency in identifying the minimum dose that achieves satisfactory efficacy. Compared to conventional designs, these trials have higher probabilities of identifying lower doses while reducing the risks of both population- and subject-level underdosing. We strongly recommend that, upon demonstration of a drug's efficacy, pandemic drug development swiftly proceeds with response-adaptive dose-finding trials. This unified strategy ensures that scarce effective drugs produce maximum social benefits