Pharmacy and Pharmaceutical Sciences Commons^™

The Mechanism Of Pda-Peg/Copper Selectively Killing Cancer Cells And Its Application In Treating Triple-Negative Breast Cancer And Advanced Ovarian Cancer, Xiangxiang Hu

Theses and Dissertations

Cancer is one of the leading modality diseases. The number of cancer patients has increased in the last decades due to radiation, aging, stress condition, and other reasons. There are three traditional cancer therapies (radiation therapy, chemotherapy, and surgery). Even though these treatments improve the life span of cancer patients, many cancer patients still lost their lives due to the development of tolerance. Thus, it is urgent to develop new kinds of treatments to extend the life span of patients. In recent decades, nanomedicine, which utilizes nanotechnology to deliver chemotherapy agents into tumor sites and improve the anticancer effect and …

Pd-L1 Nano-Eraser: A Novel Intracellular Pd-L1 Degradation Approach And Its Application In Cancer And Alzheimer’S Disease Therapy, Mingming Wang

Theses and Dissertations

Nanoparticle-based targeted therapeutics have revolutionized the field of pharmaceutics by providing precise and efficient drug delivery systems. These therapeutics utilize nanoparticles as carriers to transport drugs selectively to the target site, reducing side effects and enhancing therapeutic efficacy. Although significant advancements have been made in nano-targeted therapies, there are many challenges that need to be addressed to fully realize their potential.

In this study, we proposed a novel approach to extend the potential application of anti-Programmed Death Ligand 1 (PD-L1) antibody (aPDL1) in cancer treatment and Alzheimer’s disease therapy by leveraging the Trim-Away pathway. aPDL1-based Trim-Away involves tagging target PD-L1 …

Controlled Release Of Dna Binding Anticancer Drugs From Gold Nanoparticles With Near-Infrared Radiation, Gracie Fitzgerald, Daniel Low, Luc Morgan, Cole Hilt, Micai Benford, Caleb Akers, Skyler Hornback, J. Zach Hilt, Daniel Scott

UK CARES Faculty Publications

Traditional chemotherapies target rapidly developing cells in the human body resulting in harsh side effects including fatigue, immune system suppression, and nausea, among others. Delivery systems to focus the active pharmaceutical ingredients (APIs) to the diseased tissue can diminish the negative side effects while improving treatment outcomes. Gold nanoparticles (AuNP) offer many unique advantages as drug delivery vehicles, including being biologically inert, easily adaptable to various shapes and sizes, able to create a strong Au-thiol bond, and able to generate heat upon the absorption of near-infrared light. To this end, a AuNP delivery vehicle was engineered to load and release …

Modified Linear Peptides Effectively Silence Stat-3 In Breast Cancer And Ovarian Cancer Cell Lines, Dindyal Mandal, Sandeep Lohan, Muhammad Imran Sajid, Abdulelah Alhazza, Rakesh Kumar Tiwari, Keykavous Parang, Hamidreza Montazeri Aliabadi

Pharmacy Faculty Articles and Research

RNA interference (RNAi) has drawn enormous attention as a powerful tool because of its capability to interfere with mRNA and protein production. However, designing a safe and efficient delivery system in RNAi therapeutics remains challenging. Herein, we have designed and synthesized several linear peptides containing tryptophan (W) and arginine (R) residues separated by the β-alanine (βA) spacer and attached to a lipophilic fatty acyl chain, cholesterol, or PEG. The peptide backbone sequences were: Ac-C-βA-βA-W4-βA-βA-R4-CO-NH2 and Ac-K-βA-βA-W4-βA-βA-R4-CO-NH2, with only a difference in N-terminal amino acid. The cysteine side chain in the first sequence was used for the conjugation with PEG2000 and …

Genetic And Pharmacogenetics Associations Of Cancer Disparities In Appalachia, Nan Lin

Theses and Dissertations--Pharmacy

Individuals residing in Appalachian regions have significant health disparities, including higher cancer incidence and mortality rates. Previous studies have addressed the impact of socioeconomic status and environmental risk factors on Appalachia cancer disparities, while few studies have evaluated genetic risk factors.

Germline whole exome sequencing samples from 7,078 individuals with cancer (759 Appalachians) were evaluated. Demographics and relatedness were assessed using KING. Ethnicity was verified by principal component analysis using TRACE, which included 6,034 individuals (85%) of European genetic ancestry. After QC filtering, 5,980 individuals were analyzed. To assess the overall predisposition of hereditary disease, gene level frequency of likely …

Investigation Of Folate-Poly(Glutamic Acid)/Polyethylenimine/Dna Complexes For In Vitro Gene Delivery, Caleb Akers

Theses and Dissertations--Pharmacy

Gene therapy is currently being studied as a treatment for a variety of indications, including cancer, infectious disease, and cardiovascular diseases, among others. While many of the early treatments in the field involved the use of viral delivery methods, various safety, ethical, and financial concerns limit the potential uses of this methodology. As such, more recent research has focused on developing non-viral delivery platforms to alleviate some of the issues inherent in viral delivery. Recently, the release of the COVID-19 vaccines from Pfizer and Moderna represents a promising use of non-viral delivery as both utilized a lipid-based delivery vector.

Despite …

Long-Term Prescription Opioid Use, Cancer Stage, And Economic Burden Among Older Cancer Survivors With Non-Cancer Chronic Pain Conditions, Rudi Safarudin

Graduate Theses, Dissertations, and Problem Reports (ETD)

Opioids are commonly prescribed to treat pain conditions, which are highly prevalent among older adults (≥65 years). Recent evidence shows that opioids may have carcinogenic effects through immunosuppression and free-radical pathways, which could promote cancer growth. Two population-based studies have reported an association of opioid use with incident cancer. Many individuals with non-cancer chronic pain conditions (NCPCs) may use opioids for a long term. However, the association of long-term prescription opioid (LPO) use with cancer stage at diagnosis is still unknown. Furthermore, evidence suggests that individuals with cancer and pre-existing NCPCs may persistently use opioids, even in the absence of …

Identifying Unexpected Inflammation Resulting From Drug-Drug Interactions, Keegan Jolly

All Master's Theses

Adverse drug events result in nearly 1.3 million emergency room visits per year in the United States of America. As much as 30% of these adverse events are a result of drug-drug interactions (DDI’s). There is a gap in knowledge concerning these DDI outcomes especially when it comes to inflammation. Inflammation is linked to a variety of chronic health conditions and non-infectious diseases such as cancer. Purpose: The goal of this study was to examine how many active drug ingredients from FDA’s Adverse Event Reporting System (FAERS), when combined (in groups of two or more), elicit an inflammatory response …

Nurse-Led Education On Oral Chemotherapy Medications, Carmen Lucia Glick Alonso

Master's Projects and Capstones

Problem: Breast cancer is one of the leading causes of cancer death among women in the United States. Annually, around 264,000 breast cancer cases are diagnosed in women and 2,400 in men (Centers for Disease Control and Prevention, 2022). According to the American Cancer Society, the risk of a woman in the United States being diagnosed with breast cancer in their life is around 13% (2022).

Context: Along with a cancer diagnosis comes the need to introduce patient education about new oral chemotherapy treatments. As a treatment team member, the oncology nurse plays a vital role in this …

Development Of Peptidomimetic Inhibitors Targeting The Polo Box Domain Of Plk1 As Potential Cancer Therapeutics, Jessy Mariam Stafford

Theses and Dissertations

PLK1 overexpression has shown to be associated with tumor progression and an unfavorable prognosis in a wide variety of cancer types. Interfering with PLK1 genetically and chemically induces apoptotic cell death in cancer cells thus confirming PLK1 as a validated anticancer target. From a drug discovery perspective, PLK1 offers two functionally distinct, essential, and interconnected target sites in one molecule. These are the ATP binding kinase domain (KD) and the unique Polo Box Domain (PBD), where the interplay between these results in dynamic structural regulation of catalytic activity and sub cellular localization. Since the KD is conserved among kinases and …

Abstracts From The 2022 Health Care Systems Research Network (Hcsrn) Annual Conference

Journal of Patient-Centered Research and Reviews

The Health Care Systems Research Network (HCSRN) is comprised of 20 health systems with embedded research units. The network’s annual conference serves as a forum for research teams from member institutions to disseminate scientific findings, explore new collaborations, and share insights about conducting research in real-world care delivery settings. Abstracts accepted for presentation at HCSRN 2022 are published in this supplement of Journal of Patient-Centered Research and Reviews, the official journal of HCSRN’s annual conference proceedings.

Identification Of Translesion Synthesis Inhibitors That Target Rev7/Rev3 Protein-Protein Interactions, Seema Patel

Honors Scholar Theses

Translesion synthesis (TLS) is a cellular mechanism utilized by cancer cells to tolerate DNA damage caused by chemotherapeutics, like cisplatin, by replicating past unrepaired lesions. This increases the rate of mutations, which leads to the emergence of drug-resistant cancer cells. Preliminary studies have shown that disrupting the protein-protein interactions (PPI) in the TLS heteroprotein complex increases cells’ sensitivity to first-line genotoxic chemotherapy, illustrating how inhibiting TLS assembly and function can significantly increase cancer cell death. These results underscore the therapeutic potential of targeting TLS PPI. Our current work in this area is focusing on inhibitors capable of disrupting the Rev7/Rev3 …

The Effects Of Paclitaxel On Cellular Migration And The Cytoskeleton, Ashley Salguero-Gonzalez

Thinking Matters Symposium

In a clinical setting, some patients are exposed to an anti-cancer chemotherapy agent, paclitaxel. Cancerous cells undergo rapid, continuous cell division without control. Chemotherapy treatments try to slow and stop the uncontrollable cell division cycles and eliminate cancerous cells in the process. Paclitaxel serves as a treatment for some types of cancers, including lung, melanoma, bladder, and esophageal. Because it targets the cytoskeleton, paclitaxel can also influence cell migration. This project utilizes a cellular migration assay and an immunohistochemistry assay to analyze the effects of paclitaxel on the movement of cells and on the cytoskeleton of neuroglia rat cells with …

Mediator Kinase Inhibitors For Breast Cancer Therapy, Xiaokai Ding

Theses and Dissertations

Breast cancers (BrCa) that overexpress oncogenic tyrosine kinase receptor HER2 are treated with HER2-targeting antibodies (such as trastuzumab) or small-molecule kinase inhibitors (such as lapatinib). However, most patients with metastatic HER2+ BrCa have intrinsic resistance and nearly all eventually become resistant to HER2-targeting therapy. Resistance to HER2-targeting drugs frequently involves transcriptional reprogramming associated with constitutive activation of different signaling pathways. We have investigated the role of CDK8/19 Mediator kinase, a regulator of transcriptional reprogramming, in the response of HER2+ BrCa to HER2-targeting drugs. Selective CDK8/19 inhibitors (senexin B and SNX631) showed synergistic interactions with lapatinib and trastuzumab in a panel …

Editorial: Anticancer Potential Of Artemisia Annua, Jill M. Kolesar, Peter H. Seeberger

Pharmacy Practice and Science Faculty Publications

No abstract provided.

Incidence Of Cancer, Depression, And Economic Burden Of Prescription Nsaids Among Older Adults With Osteoarthritis: Statistical And Machine Learning Approaches, Nazneen Fatima Mohammed Umer Shaikh

Graduate Theses, Dissertations, and Problem Reports (ETD)

Understanding the role of chronic inflammation among older adults is critical because of its implications on chronic inflammatory conditions as well as its interaction with anti-inflammatory medications. Osteoarthritis (OA) is a heterogeneous multi-faceted joint disease with multi-tissue involvement of varying severity, and increasing evidence demonstrates a key role of chronic inflammation in its pathogenesis. Approximately 30 million adults in the United States have OA, and it is reported that a large proportion (43%) of them are older than 65 years. OA is typically treated using non-steroidal anti-inflammatory drugs (NSAIDs) for minimizing pain and reducing inflammation. NSAIDs have consistently shown clinically …

Optimization Of The Structure Of Ttr Ligands For Half-Life Extension (Tlhe), Guanming Jiang

University of the Pacific Theses and Dissertations

Many potential therapeutic agents face challenges for their clinical development due to short circulation half-life. As a result, prolonging the half-life of therapeutic drugs in circulation while preserving their hydrophilicity and small size will be a key step toward more effective and safe pharmacological molecules. Our lab developed a new approach for enhancing the safety and efficacy of therapeutic agents. By endowing therapeutic agents with a hydrophilic small molecule (a derivative of the clinical candidate, AG10) which reversibly binds to the serum protein transthyretin (TTR), the half-life of the therapeutic agent should be extended by binding to the TTR in …

Design And Synthesis Of Curcumin Analogs For Anticancer Activity And Discovery Of Novel Hit Molecules Targeting Cxcr4., Maryam Sadat Hosseini Zare

Dissertations (2016-Present)

Curcumin as a natural compound is made of various components including protein, carbohydrate, and curcuminoid. Curcuminoid is made of curcumin, desmethoxycurcumin and bis desmethoxycurcumin. Curcumin is used for the treatment of cancer and inflammatory disorders, but it has some therapeutic problems like poor bioavailability, poor efficacy, and chemical instability. To overcome these problems, the objective of this study is (1) synthesis of pyrazole curcumin analogs, (2) synthesis of triazole curcumin analogs, and (3) in-vitro study of the anticancer activity of these curcumin analogs on head & neck, breast, pancreatic and glioblastoma cancer cells. During this part of my Ph.D. project, …

The Global Burden Of Adolescent And Young Adult Cancer In 2019: A Systematic Analysis For The Global Burden Of Disease Study 2019, Elysia M. Alvarez, Lisa M. Force, Rixing Xu, Kelly Compton, Dan Lu, Ismaeel Yunusa Ph. D., Et Al.

Faculty Publications

Background

Methods

Conference Proceedings: Select Abstracts Presented At 2021 Advocate Aurora Health Scientific Day

Journal of Patient-Centered Research and Reviews

Abstracts published within this supplement were presented at the 47th annual Advocate Aurora Health Scientific Day, held virtually on May 26, 2021. This research symposium provides a forum for disseminating results from studies conducted by faculty, fellows, residents, and other allied health professionals associated with Midwest-based health system Advocate Aurora Health, which publishes the Journal of Patient-Centered Research and Reviews.

The Development Of Novel Cdk8 And Cdk19 Inhibitors And Degraders As Potential Anti-Cancer Agents, Li Zhang

Theses and Dissertations

CDK8 and its homolog CDK19 are essential for transcription regulation and their dysregulation has been identified in numerous diseases, especially in cancers. CDK8 and CDK19 have been implicated in cancer development through their kinase activity and kinase independent functions. Despite the existing CDK8/19 inhibitors, there is still a need to develop novel CDK8/19 inhibitors with improved potency and PK profile. It is also necessary to develop CDK8/19 degraders that are able to eliminate the kinase-independent functions. Although two CDK8-degrading PROteolysis Activating Chimeras (PROTACs) have been reported, they have limited CDK8 degradation efficacy and no effect on CDK19. PROTACs with improved …

Design And Application Of Hybrid Cyclic-Linear Peptide-Doxorubicin Conjugates As A Strategy To Overcome Doxorubicin Resistance And Toxicity, Saghar Mozaffari, David Salehi, Parvin Mahdipoor, Richard Beuttler, Rakesh Tiwari, Hamidreza Montazeri Aliabadi, Keykavous Parang

Pharmacy Faculty Articles and Research

Doxorubicin (Dox) is used for breast cancer, leukemia, and lymphoma treatment as an effective chemotherapeutic agent. However, Dox use is restricted due to inherent and acquired resistance and an 8-fold increase in the risk of potentially fatal cardiotoxicity. Hybrid cyclic-linear peptide [R5K]W7A and linear peptide R5KW7A were conjugated with Dox through a glutarate linker to afford [R5K]W7A-Dox and R5KW7A-Dox conjugates to generate Dox derivatives. Alternatively, [R5K]W7C was conjugated with Dox via a disulfide linker to generate [R5K]W7C–S–S-Dox conjugate, where S–S is a disulfide bond. Comparative antiproliferative assays between conjugates [R5K]W7A-Dox, [R5K]W7C–S–S-Dox, linear R5KW7A-Dox, the corresponding physical mixtures of the peptides, …

Real-World Evaluation Of Universal Germline Screening For Cancer Treatment-Relevant Pharmacogenes, Megan L. Hutchcraft, Nan Lin, Shulin Zhang, Catherine Sears, Kyle Zacholski, Elizabeth A. Belcher, Eric B. Durbin, John L. Villano, Michael J. Cavnar, Susanne M. Arnold, Frederick R. Ueland, Jill M. Kolesar

Pathology and Laboratory Medicine Faculty Publications

The purpose of this study was to determine the frequency of clinically actionable treatment-relevant germline pharmacogenomic variants in patients with cancer and assess the real-world clinical utility of universal screening using whole-exome sequencing in this population. Cancer patients underwent research-grade germline whole-exome sequencing as a component of sequencing for somatic variants. Analysis in a clinical bioinformatics pipeline identified clinically actionable pharmacogenomic variants. Clinical Pharmacogenetics Implementation Consortium guidelines defined clinical actionability. We assessed clinical utility by reviewing electronic health records to determine the frequency of patients receiving pharmacogenomically actionable anti-cancer agents and associated outcomes. This observational study evaluated 291 patients with …

Clinical Correlations Of Polycomb Repressive Complex 2 In Different Tumor Types, Maksim Erokhin, Olga Chetverina, Balázs Győrffy, Victor V. Tatarskiy, Vladic Mogila, Alexander A. Shtil, Igor Roninson, Jerome Moreaux, Pavel Georgiev, Giacomo Cavalli, Darya Chetverina

Faculty Publications

PRC2 (Polycomb repressive complex 2) is an evolutionarily conserved protein complex required to maintain transcriptional repression. The core PRC2 complex includes EZH2, SUZ12, and EED proteins and methylates histone H3K27. PRC2 is known to contribute to carcinogenesis and several small molecule inhibitors targeting PRC2 have been developed. The present study aimed to identify the cancer types in which PRC2 targeting drugs could be beneficial. We queried genomic and transcriptomic (cBioPortal, KMplot) database portals of clinical tumor samples to evaluate clinical correlations of PRC2 subunit genes. EZH2, SUZ12, and EED gene amplification was most frequently found in prostate cancer, whereas lymphoid …

Ethiopian Medicinal Plants Traditionally Used For The Treatment Of Cancer; Part 3: Selective Cytotoxic Activity Of 22 Plants Against Human Cancer Cell Lines, Solomon Tesfaye, Hannah Braun, Kaleab Asres, Ephrem Engidawork

Faculty and Student Publications

Medicinal plants have been traditionally used to treat cancer in Ethiopia. However, very few studies have reported the in vitro anticancer activities of medicinal plants that are collected from different agro‐ecological zones of Ethiopia. Hence, the main aim of this study was to screen the cytotoxic activities of 80% methanol extracts of 22 plants against human peripheral blood mononuclear cells (PBMCs), as well as human breast (MCF‐7), lung (A427), bladder (RT‐4), and cervical (SiSo) cancer cell lines. Active extracts were further screened against human large cell lung carcinoma (LCLC‐103H), pancreatic cancer (DAN‐G), ovarian cancer (A2780), and squamous cell carcinoma of …

Design And Synthesis Of Macrocyclic Peptide Braf-Wt Dimerization Inhibitors For The Treatment Of Metastatic Melanoma, Chad Mulloy Beneker

Theses and Dissertations

In cases of metastatic melanoma, BRAF is frequently mutated to the V600E oncoprotein causing uncontrolled cell proliferation driven by the MAPK-ERK pathway. There are several BRAF inhibitors, such as vemurafenib, which are FDA approved, but patients treated with these Type-I kinase inhibitors frequently observe relapse under mutant RAS and BRAF-wt conditions due to paradoxical activation. The mechanism of this resistance occurs through binding of the inhibitor to BRAF-wt initiating conformational changes which leads to BRAF dimerization. Once in the dimerized state, the inhibited monomer induces allosteric transactivation of the second monomer. This drug-induced activation of BRAF in cells with mutant …

[(Wr)8Wkβa]-Doxorubicin Conjugate: A Delivery System To Overcome Multi-Drug Resistance Against Doxorubicin, Khalid Zoghebi, Hamidreza Montazeri Aliabadi, Rakesh Kumar Tiwari, Keykavous Parang

Pharmacy Faculty Articles and Research

Doxorubicin (Dox) is an anthracycline chemotherapeutic agent used to treat breast, leukemia, and lymphoma malignancies. However, cardiotoxicity and inherent acquired resistance are major drawbacks, limiting its clinical application. We have previously shown that cyclic peptide [WR]₉ containing alternate tryptophan (W) and arginine (R) residues acts as an efficient molecular transporter. An amphiphilic cyclic peptide containing a lysine (K) residue and alternative W and R was conjugated through a free side chain amino group with Dox via a glutarate linker to afford [(WR)₈WKβA]-Dox conjugate. Antiproliferative assays were performed in different cancer cell lines using the conjugate and the …

A Global Review On Short Peptides: Frontiers And Perspectives, Vasso Apostolopoulos, Joanna Bojarska, Tsun-Thai Chai, Sherif Elnagdy, Krzysztof Kaczmarek, John Matsoukas, Roger New, Keykavous Parang, Octavio Paredes Lopez, Hamideh Parhiz, Conrad O. Perera, Monica Pickholz, Milan Remko, Michele Saviano, Mariusz Skwarczynski, Yefeng Tang, Wojciech M. Wolf, Taku Yoshiya, Janusz Zabrocki, Piotr Zielenkiewicz, Maha Alkhazindar, Vanessa Barriga, Konstantinos Kelaidonis, Elham Mousavinezhad Sarasia, Istvan Toth

Pharmacy Faculty Articles and Research

Peptides are fragments of proteins that carry out biological functions. They act as signaling entities via all domains of life and interfere with protein-protein interactions, which are indispensable in bio-processes. Short peptides include fundamental molecular information for a prelude to the symphony of life. They have aroused considerable interest due to their unique features and great promise in innovative bio-therapies. This work focusing on the current state-of-the-art short peptide-based therapeutical developments is the first global review written by researchers from all continents, as a celebration of 100 years of peptide therapeutics since the commencement of insulin therapy in the 1920s. …

Mechanisms Of Apoptosis Induced By Actinomycin D In Aerodigestive Tract Cancers, Adeoluwa Ayodeji Adeluola

Theses, Dissertations and Capstones

Upper aerodigestive tract cancers including cancers of the oral cavity, pharynx, larynx, esophagus, and lungs are the most prevalent cancers and leading causes of cancer-related deaths. Collectively, over 300,000 new cases and 146,500 deaths are projected within the US in the year 2021. Drug-associated toxicities, as well as resistance to therapy (intrinsic and acquired), are big challenges for successfully treating these cancers. Recent studies have shown that combining low-dose actinomycin D with existing therapies is a promising strategy to reduce toxicity (cyclotherapy) and to overcome resistance. The development of these treatment strategies however requires an understanding of the molecular mechanisms …

Rasburicase Utilization After Protocol Implementation Focused On Fixed Dosing By Limiting Use Of Weight-Based Dosing To Oncology Providers, Dakota Smith Bs, Jamie Gaul Pharmd, Bcps, Liam Dadey Pharmd, Bcps

Parkview Pharmacy Department

Dec 2021 ASHP Midyear Clinical Meeting / Poster

Objective: Evaluate the change in rasburicase use pre- and post-implementation of dosing restriction protocol.