Preparation of a New Library of Thermally Sensitive End-Caps for Self-Immolative Polymers as a Potential Drug-Delivery Method

Triggerable end-caps are a fascinating new tool in the field of material, environment and medicinal sciences that can be used for a variety of applications including the on-command degradation of self-immolative polymers. These end caps can be made sensitive to a diverse range of parameters including light, pH and enzymes. However, using heat might be of great utility for biomedical applications as it can be localized to a specific site through a number of non-invasive methods. The Trant group has prepared a number of heat-sensitive end-caps, and this study extends the scope and temperature range available to us by modifying the basic structure. These are synthesized through an efficient Diels-Alder reaction between a substituted furan and maleimide that allows for reversibility at a range of temperatures: the temperature at which the end-caps undergo retro-Diels-Alder reactions can be controlled through functionalization of these components. The role of furan functionalization with various electron donating and withdrawing groups was investigated, however steric effects played a significant role in the formation of the end-caps and it was difficult to determine the electronic effect on end-cap stability. To overcome this, furans with various para-substituted phenyls covering a range of electron withdrawing and donating groups were utilized where the steric effects are minimized, allowing the electronic effects to be investigated. This will improve our understanding of these end-caps and allow us to create a library of end-caps covering a broad range of degradation temperatures which can then be used for a variety of applications. This presentation will discuss the design, synthesis, and applications of these new thermally-sensitive molecules

Pillararenes: Tubular-shaped artificial receptors. Cavitands Part 2

Pillararenes: Tubular-shaped artificial receptors. Cavitands Part 2 Emma Dennison, Daniel Meister, Michael Reynolds, N. Kodiah Beyeh, John F. Trant Macrocycles are important supramolecular scaffolds for host-guest chemistry and offer a wide array of potential applications.1 This may range from design of synthetic catalysts, to the slow release of drug molecules, to the preparation of targeted sensors.2 Pillararenes have attracted considerable attention due to the large size of their cavity, and the fact that they are open at both ends, allowing them to bind large linear molecules such as DNA and proteins.4-5 Additionally, they can be modified with numerous functional groups allowing for tunable molecular recognition of a wide array of desired substrates.4 Synthesis of large pillararenes is challenging as they are entropically disfavoured. Pillar[5]arene is the mostly widely studied as it can be synthesized cheaply in high yields.4 For our purposes—binding single stranded DNA for the delivery of new types of biologics drugs—we require a larger cavity, such as pillar[7]arene or larger, to accommodate biological molecules (the number indicates the number of repeating subunits in the ring, larger numbers means a larger hole). We have designed and synthesized novel pillar[7]arenes which can be utilized as a binder for proteins and viruses, creating a supramolecular complex with two binding sites which has potential for dual-sensing or catalysis. Additionally, they may be combined with ferritin to create self-assembling biomolecular magnetic nanoparticles, or due to their large size, used to bind DNA. This presentation is an introduction to host-guest chemistry as it relates to pillararenes, and will discuss their synthesis and potential applications using examples from our lab. References 1 Liu, Z.; Nalluri, S. K. M.; Stoddart, J. F. Surveying macrocyclic chemistry: from flexible crown ethers to rigid cyclophanes. Chem. Soc. Rev. 2017, 46, 2459–2478. 2 S. Guha S.; Saha, S. Fluoride Ion Sensing by an Anion−π Interaction. J. Am. Chem. Soc., 2010, 132, 17674–17677. 3. Xue, M., Yang, Y., Chi, X., Zhang, Z. & Huang, F. Pillararenes, a new class of macrocycles for supramolecular chemistry. Acc. Chem. Res. 2012, 45, 1294–1308. 4. Shi, B.; Guan, H.; Shangguan, L.; Wang, H.; Xia, D.; Kong, X.; Huang, F. A pillar[5]arene-based 3D network polymer for rapid removal of organic micropollutants from water. J. Mater. Chem. A. 2017, 5, 24217–24222

Senior Resource Alliance Needs Assessment 2018

The University of Central Florida’s Institute for Social and Behavioral Science (ISBS) conducted a needs assessment on behalf of the Senior Resource Alliance

Senior Resource Alliance Needs Assessment 2018: Final Report

The University of Central Florida’s Institute for Social and Behavioral Science (ISBS) conducted a needs assessment on behalf of the Senior Resource Alliance. The needs assessment consisted of a survey with 400 senior respondents in PSA 7 as well as secondary data analysis. Specifically the secondary data analysis focused on three components: 1. Demographic report on the population age 60+, 65+, and 85+, showing the most recent data at the local, state, and national level; 2. Statistical summaries of target populations and target areas in PSA 7; and 3. Population projections on the baby boomer cohort data. The University of Central Florida’s Institute for Social and Behavioral Sciences (ISBS) conducted a needs assessment on behalf of the Senior Resource Alliance. The needs assessment consisted of a survey with 400 senior respondents in PSA 7 as well as secondary data analysis. Specifically the secondary data analysis focused on three components: 1. Demographic report on the population age 60+, 65+, and 85+, showing the most recent data at the local, state, and national level; 2. Statistical summaries of target populations and target areas in PSA 7; and 3. Population projections on the baby boomer cohort data

A Multivalent Approach to Triggerable-Release Cancer Drug Delivery Systems

Cancer continues to be one of the largest health concerns in Canada with approximately 43% of Canadians expected to be diagnosed in their lifetime. However, traditional chemotherapy methods often create complications from nonspecific drug distribution and poor penetration into tumors, providing an inefficient method for suppressing tumor growth and metastasis, and causing indiscriminate harm to healthy cells in the body. The damage that is caused to healthy cells is the root of most destructive and painful side-effects associated with chemotherapy, including nausea, fatigue, hair loss, mouth sores, fertility issues, and organ damage . Nanodiamonds, microscopic diamond particles, have recently gained popularity in medical applications due to their low cost and negligible toxicity. Additionally, their large surface area allows them to be easily modified with biocompatible attachments like polyethylene glycol (PEG) chains and a self-immolative drug linker, which acts as an efficient drug carrier due to its increased loading site. The Trant Team seeks to design and characterize a selective drug delivery system utilizing the pH-sensitive linker property to release the drug in the cancer cell’s acidic environment, reducing harm to not-as-acidic healthy cells. Previous work within the team used nanodiamond single valent carriers in preliminary studies. This presentation will describe multivalent modifications to further increase the loading capacity. Once synthesized and characterized, this drug delivery system is to be tested in vivo on zebrafish to observe its safety and efficacy

HoxA9 binds and represses the Cebpa +8 kb enhancer

C/EBPα plays a key role in specifying myeloid lineage development. HoxA9 is expressed in myeloid progenitors, with its level diminishing during myeloid maturation, and HOXA9 is over-expressed in a majority of acute myeloid leukemia cases, including those expressing NUP98-HOXD13. The objective of this study was to determine whether HoxA9 directly represses Cebpa gene expression. We find 4-fold increased HoxA9 and 5-fold reduced Cebpa in marrow common myeloid and LSK progenitors from Vav-NUP98-HOXD13 transgenic mice. Conversely, HoxA9 decreases 5-fold while Cebpa increases during granulocytic differentiation of 32Dcl3 myeloid cells. Activation of exogenous HoxA9-ER in 32Dcl3 cells reduces Cebpa mRNA even in the presence of cycloheximide, suggesting direct repression. Cebpa transcription in murine myeloid cells is regulated by a hematopoietic-specific +37 kb enhancer and by a more widely active +8 kb enhancer. ChIP-Seq analysis of primary myeloid progenitor cells expressing exogenous HoxA9 or HoxA9-ER demonstrates that HoxA9 localizes to both the +8 kb and +37 kb Cebpa enhancers. Gel shift analysis demonstrates HoxA9 binding to three consensus sites in the +8 kb enhancer, but no affinity for the single near-consensus site present in the +37 kb enhancer. Activity of a Cebpa +8 kb enhancer/promoter-luciferase reporter in 32Dcl3 or MOLM14 myeloid cells is increased ~2-fold by mutation of its three HOXA9-binding sites, suggesting that endogenous HoxA9 represses +8 kb Cebpa enhancer activity. In contrast, mutation of five C/EBPα-binding sites in the +8 kb enhancer reduces activity 3-fold. Finally, expression of a +37 kb enhancer/promoter-hCD4 transgene reporter is reduced ~2-fold in marrow common myeloid progenitors when the Vav-NUP98-HOXD13 transgene is introduced. Overall, these data support the conclusion that HoxA9 represses Cebpa expression, at least in part via inhibition of its +8 kb enhancer, potentially allowing normal myeloid progenitors to maintain immaturity and contributing to the pathogenesis of acute myeloid leukemia associated with increased HOXA9

A murine preclinical syngeneic transplantation model for breast cancer precision medicine

We previously demonstrated that altered activity of lysophosphatidic acid in murine mammary glands promotes tumorigenesis. We have now established and characterized a heterogeneous collection of mouse-derived syngeneic transplants (MDSTs) as preclinical platforms for the assessment of personalized pharmacological therapies. Detailed molecular and phenotypic analyses revealed that MDSTs are the most heterogeneous group of genetically engineered mouse models (GEMMs) of breast cancer yet observed. Response of MDSTs to trametinib, a mitogen-activated protein kinase (MAPK) kinase inhibitor, correlated with RAS/MAPK signaling activity, as expected from studies in xenografts and clinical trials providing validation of the utility of the model. Sensitivity of MDSTs to talazoparib, a poly(adenosine 5′-diphosphate–ribose) polymerase (PARP) inhibitor, was predicted by PARP1 protein levels and by a new PARP sensitivity predictor (PSP) score developed from integrated analysis of drug sensitivity data of human cell lines. PSP score–based classification of The Cancer Genome Atlas breast cancer suggested that a subset of patients with limited therapeutic options would be expected to benefit from PARP-targeted drugs. These results indicate that MDSTs are useful models for studies of targeted therapies, and propose novel potential biomarkers for identification of breast cancer patients likely to benefit from personalized pharmacological treatments

A Blood-Based Metabolomic Signature Predictive of Risk for Pancreatic Cancer

Emerging evidence implicates microbiome involvement in the development of pancreatic cancer (PaCa). Here, we investigate whether increases in circulating microbial-related metabolites associate with PaCa risk by applying metabolomics profiling to 172 sera collected within 5 years prior to PaCa diagnosis and 863 matched non-subject sera from participants in the Prostate, Lung, Colorectal, and Ovarian (PLCO) cohort. We develop a three-marker microbial-related metabolite panel to assess 5-year risk of PaCa. The addition of five non-microbial metabolites further improves 5-year risk prediction of PaCa. The combined metabolite panel complements CA19-9, and individuals with a combined metabolite panel + CA19-9 score in the top 2.5th percentile have absolute 5-year risk estimates of \u3e13%. The risk prediction model based on circulating microbial and non-microbial metabolites provides a potential tool to identify individuals at high risk of PaCa that would benefit from surveillance and/or from potential cancer interception strategies

Lead-Time Trajectory of CA19-9 as an Anchor Marker for Pancreatic Cancer Early Detection

Background & Aims There is substantial interest in liquid biopsy approaches for cancer early detection among subjects at risk, using multi-marker panels. CA19-9 is an established circulating biomarker for pancreatic cancer; however, its relevance for pancreatic cancer early detection or for monitoring subjects at risk has not been established. Methods CA19-9 levels were assessed in blinded sera from 175 subjects collected up to 5 years before diagnosis of pancreatic cancer and from 875 matched controls from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. For comparison of performance, CA19-9 was assayed in blinded independent sets of samples collected at diagnosis from 129 subjects with resectable pancreatic cancer and 275 controls (100 healthy subjects; 50 with chronic pancreatitis; and 125 with noncancerous pancreatic cysts). The complementary value of 2 additional protein markers, TIMP1 and LRG1, was determined. Results In the PLCO cohort, levels of CA19-9 increased exponentially starting at 2 years before diagnosis with sensitivities reaching 60% at 99% specificity within 0 to 6 months before diagnosis for all cases and 50% at 99% specificity for cases diagnosed with early-stage disease. Performance was comparable for distinguishing newly diagnosed cases with resectable pancreatic cancer from healthy controls (64% sensitivity at 99% specificity). Comparison of resectable pancreatic cancer cases to subjects with chronic pancreatitis yielded 46% sensitivity at 99% specificity and for subjects with noncancerous cysts, 30% sensitivity at 99% specificity. For prediagnostic cases below cutoff value for CA19-9, the combination with LRG1 and TIMP1 yielded an increment of 13.2% in sensitivity at 99% specificity ( P = .031) in identifying cases diagnosed within 1 year of blood collection. Conclusion CA19-9 can serve as an anchor marker for pancreatic cancer early detection applications