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Total Synthesis Of 6,7-Dimethyl-N-Methyl Aziridinomitosene, Thaaer N. Muhammed

Boise State University Theses and Dissertations

Mitomycin C (MC) is a naturally occurring antitumor agent isolated from a soil bacterium. MC is effective against solid hypoxic tumors that respond poorly to radiotherapy, such as colorectal, gastric, and lung tumors. Also, it has a role in the treatment of bladder, head and neck, and non-small cell lung cancers in combination with other chemotherapeutic.

MC and other members of the mitomycin family of antitumor agents fight cancer by forming DNA interstrand crosslinks (ICLs), which leads to apoptosis. In order to form ICLs, MC requires a reductive activation step that produces reactive oxygen species. This activation step is proposed …

Clinical Applications Of Infrared And Raman Spectroscopy: State Of Play And Future Challenges, Matthew Baker, Hugh Byrne, John Chalmers, Peter Gardner, Royston Goodacre, Alex Henderson, Sergei Kazarian, Francis Martin, Julian Moger, Nick Stone, Josep Sule-Suso

Articles

Vibrational spectroscopies, based on Infrared absorption and/or Raman scattering provide a detailed fingerprint of a material, based on the chemical content. Diagnostic and prognostic tools based on these technologies have the potential to revolutionise our clinical systems leading to improved patient outcome, more efficient public services and significant economic savings. However, despite these strong drivers, there are many fundamental scientific and technological challenges which have limited the implementation of this technology in the clinical arena, although recent years have seen significant progress in addressing these challenges. This review examines (i) the state of the art of clinical applications of infrared …

Immunostimulatory Effects Of Antigen-Conjugated Inp/Zns Quantum Dot Nanoparticles In An Avian Model, Christopher Lyle

Graduate Theses and Dissertations

Due to their unique physicochemical and enhanced immunostimulatory properties, quantum dot (QD) nanoparticles have shown increasing promise in biomedical research applications including bioimaging, drug delivery, and as vaccine adjuvants. Toxicity, however, remains a concern for the use of QD in these applications and thus, there is an increased demand for effective in vitro and in vivo systems to measure the bioactivity of QD. In this study in vitro and in vivo chicken models were used to investigate the effects of QD on innate and adaptive immunity. Chicken macrophage cultures were treated in vitro with QD to measure macrophage activation and …

Catalyzed And Uncatalyzed Modifications Of Nucleosides, Synthesis Of Hippadine, And Deuterated 1,2,3-Triazoles, Hari K. Akula

Dissertations, Theses, and Capstone Projects

The C4 amide carbonyl of O-t-butyldimethylsilyl-protected thymidine, 2’-deoxyuridine, and 3’-azidothymidine (AZT) was activated by reaction with (benzotriazol-1-yloxy)tris(dimethylamino) phosphonium hexafluorophosphate (BOP) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in THF as solvent. This led to the formation of corresponding O⁴-(benzotriazol-1-yl) derivatives, which are reactive intermediates. Substitution at the C4 position was then carried out by reactions with alkyl and aryl amines, and thiols. Typically, reactions were conducted as a two-step, one-pot transformation, and also as a one-step conversion. After examining the reactions, the formation of 1-(4-pyrimidinyl)-1H-benzotriazole-3-oxide derivatives from the pyrimidine nucleosides was identified. However, these too underwent conversion to …

The Innate Immune Response To Ischemic Injury: A Multiscale Modeling Perspective., Elena Dimitrova, Leslie A Caromile, Reinhard Laubenbacher, Linda H Shapiro

Faculty Research 2018

BACKGROUND: Cell death as a result of ischemic injury triggers powerful mechanisms regulated by germline-encoded Pattern Recognition Receptors (PRRs) with shared specificity that recognize invading pathogens and endogenous ligands released from dying cells, and as such are essential to human health. Alternatively, dysregulation of these mechanisms contributes to extreme inflammation, deleterious tissue damage and impaired healing in various diseases. The Toll-like receptors (TLRs) are a prototypical family of PRRs that may be powerful anti-inflammatory targets if agents can be designed that antagonize their harmful effects while preserving host defense functions. This requires an understanding of the complex interactions and consequences …

Opportunities And Obstacles For Deep Learning In Biology And Medicine, Travers Ching, S Joshua Swamidass, Et Al

2010-2019 OA Pubs

Deep learning describes a class of machine learning algorithms that are capable of combining raw inputs into layers of intermediate features. These algorithms have recently shown impressive results across a variety of domains. Biology and medicine are data-rich disciplines, but the data are complex and often ill-understood. Hence, deep learning techniques may be particularly well suited to solve problems of these fields. We examine applications of deep learning to a variety of biomedical problems-patient classification, fundamental biological processes and treatment of patients-and discuss whether deep learning will be able to transform these tasks or if the biomedical sphere poses unique …

Chemiluminescent Agents For In Vivo Imaging, Jian Cao

Chemistry Theses and Dissertations

Chemiluminescence is the light production directly from a highly exothermic chemical reaction by generating electronically excited species, and the light will be generated upon relaxation to the ground state. We utilize this light as the readout to construct imaging agents for reactive species. Chemiluminescence as an imaging modality has many advantages compared with current widely used imaging modalities, such as fluorescence and bioluminescence. The main advantages are the elimination of extraneous light excitation or genetic modification, which are required for fluorescence and bioluminescence imaging. Therefore, chemiluminescence as a imaging modality holds great potential for in vivo imaging.

In this dissertation, …

Acute Loss Of Iron-Sulfur Clusters Results In Metabolic Reprogramming And Generation Of Lipid Droplets In Mammalian Cells, Daniel R. Crooks, Nunziata Maio, Andrew N. Lane, Michal Jarnik, Richard M. Higashi, Ronald G. Haller, Ye Yang, Teresa Whei-Mei Fan, W. Marston Linehan, Tracey A. Rouault

Center for Environmental and Systems Biochemistry Faculty Publications

Iron–sulfur (Fe-S) clusters are ancient cofactors in cells and participate in diverse biochemical functions, including electron transfer and enzymatic catalysis. Although cell lines derived from individuals carrying mutations in the Fe-S cluster biogenesis pathway or siRNA-mediated knockdown of the Fe-S assembly components provide excellent models for investigating Fe-S cluster formation in mammalian cells, these experimental strategies focus on the consequences of prolonged impairment of Fe-S assembly. Here, we constructed and expressed dominant–negative variants of the primary Fe-S biogenesis scaffold protein iron–sulfur cluster assembly enzyme 2 (ISCU2) in human HEK293 cells. This approach enabled us to study the early metabolic reprogramming …

Lpa Signaling Is Regulated Through The Primary Cilium: A Novel Target In Glioblastoma, Yuriy V. Loskutov, Caryn L. Griffin, Kristina M. Marinak, Andrey Bobko, Naira V. Margaryan, Werner J. Geldenhuys, Jann N. Sarkaria, Elena N. Pugacheva

Clinical and Translational Science Institute

The primary cilium is a ubiquitous organelle presented on most human cells. It is a crucial signaling hub for multiple pathways including growth factor and G-protein coupled receptors. Loss of primary cilia, observed in various cancers, has been shown to affect cell proliferation. Primary cilia formation is drastically decreased in glioblastoma (GBM), however, the role of cilia in normal astrocyte or glioblastoma proliferation has not been explored. Here we report that loss of primary cilia in human astrocytes stimulates growth rate in a lysophosphatidic acid (LPA)-dependent manner. We show that lysophosphatidic acid receptor 1 (LPAR1) is accumulated in primary cilia. …

Novel Fluconazole Derivatives With Promising Antifungal Activity, Nishad Thamban Chandrika, Sanjib K. Shrestha, Huy X. Ngo, Kaitlind C. Howard, Sylvie Garneau-Tsodikova

Pharmaceutical Sciences Faculty Publications

The fungistatic nature and toxicity concern associated with the azole drugs currently on the market have resulted in an increased demand for new azole antifungal agents for which these problematic characteristics do not exist. The extensive use of azoles has resulted in fungal strains capable of resisting the action of these drugs. Herein, we report the synthesis and antifungal activities of novel fluconazole (FLC) analogues with alkyl-, aryl-, cycloalkyl-, and dialkyl-amino substituents. We evaluated their antifungal activity by MIC determination and time-kill assay as well as their safety profile by hemolytic activity against murine erythrocytes as well as cytotoxicity against …

Parp Pet Imaging Agents, Brandon Carney

Dissertations, Theses, and Capstone Projects

The poly (adenosine-diphosphate (ADP) ribose) polymerase (PARP) family of enzymes has been of interest to researchers and clinicians for over fifty years, especially the first member of the family, PARP1. This enzyme has become a target for cancer therapeutics due the reliance of highly proliferating cells on PARP1 for genomic maintenance. In the coming age of individualized medicine, however, highly specific therapeutic agents like PARP inhibitors are in need of similarly highly specific companion diagnostic agents. These kind of agents have been made possible with the quickly progressing field of molecular imaging. Specifically, positron emission tomography (PET) has enabled the …

Ependymomas Overexpress Chemoresistance And Dna Repair-Related Proteins., Sherise D Ferguson, Shouhao Zhou, Joanne Xiu, Yuuri Hashimoto, Nader Sanai, Lyndon Kim, Santosh Kesari, John De Groot, David Spetzler, Amy B Heimberger

Articles, Abstracts, and Reports

Background: After surgery and radiation, treatment options for ependymoma are few making recurrence a challenging issue. Specifically, the efficacy of chemotherapy at recurrence is limited. We performed molecular profiling on a cohort of ependymoma cases in order to uncover therapeutic targets and to elucidate the molecular mechanisms contributing to treatment resistance.

Results: This ependymoma cohort showed minimal alterations in gene amplifications and mutations but had high expression rates of DNA synthesis and repair enzymes such as RRM1 (47%), ERCC1 (48%), TOPO1 (62%) and class III β-tublin (TUBB3) (57%), which are also all associated with chemoresistance. This cohort also had high …

Surgical Interventions For Advanced Parameningeal Rhabdomyosarcoma Of Children And Adolescents., Paul J Choi, Joe Iwanaga, R Shane Tubbs, Emre Yilmaz

Articles, Abstracts, and Reports

Owing to its rarity, rhabdomyosarcoma of the head and neck (HNRMS) has seldom been discussed in the literature. As most of the data is based only on the retrospective experiences of tertiary healthcare centers, there are difficulties in formulating a standard treatment protocol. Moreover, the disease is poorly understood at its pathological, genetic, and molecular levels. For instance, 20% of all histological assessment is inaccurate; even an experienced pathologist can confuse rhabdomyosarcoma (RMS) with neuroblastoma, Ewing's sarcoma, and lymphoma. RMS can occur sporadically or in association with genetic syndromes associated with predisposition to other cancers such as Li-Fraumeni syndrome and …

Design And Synthesis Of Small Molecule Agonists Of Epha2 Receptor, Aaron Petty, Nethrie Idippily, Viharika Bobba, Werner J. Geldenhuys, Bo Zhong, Bin Su, Bingcheng Wang

Clinical and Translational Science Institute

Ligand-independent activation of EphA2 receptor kinase promotes cancer metastasis and invasion. Activating EphA2 receptor tyrosine kinase with small molecule agonist is a novel strategy to treat EphA2 overexpressing cancer. In this study, we performed a lead optimization of a small molecule Doxazosin that was identified as an EphA2 receptor agonist. 33 new analogs were developed and evaluated; a structure−activity relationship was summarized based on the EphA2 activation of these derivatives. Two new derivative compounds 24 and 27 showed much improved activity compared to Doxazosin. Compound 24 possesses a bulky amide moiety, and compound 27 has a dimeric structure that is …

Allicin- Inspired Pyridyl Disulfides As Antimicrobial Agents For Multidrug-Resistant Staphylococcus Aureus, Jordan G. Sheppard, Jeremy P. Mcaleer, Pushkar Saralkar, Werner J. Geldenhuys, Timothy E. Long

Clinical and Translational Science Institute

A chemical library comprised of nineteen synthesized pyridyl disulfides that emulate the chemical reactivity of allicin (garlic) was evaluated for antimicrobial activity against a panel of pathogenic bacteria. Gram-positive species including vancomycin-intermediate and vancomycin-resistant Staphylococcus aureus (VISA, VRSA) demonstrated the highest level of susceptibility toward analogs with S-alkyl chains of 7–9 carbons in length. Further biological studies revealed that the disulfides display synergy with vancomycin against VRSA, cause dispersal of S. aureus biofilms, exhibit low cytotoxicity, and decelerate S. aureus metabolism. In final analysis, pyridyl disulfides represent a novel class of mechanism-based antibacterial agents that have a potential application as …

Biosocial Criminology Versus The Constitution, Karen E. Balter

Regis University Student Publications (comprehensive collection)

The continually emerging field of biosocial criminology provides a basis for productively merging biology with sociological reasonings for criminal behavior. Mainstream research in criminology focuses on environmental factors as the sole reason individuals exhibit antisocial behavior patterns and may ultimately commit crimes. Criminological research has travelled in this direction for decades. The current climate within this community subscribes heavily to the notion that biology has very little to do with why people behave the way they do, and if it did, government control would be the norm. The nature of biocriminology opens a door through which constitutional issues may enter. …

The Effects Of Emerging Technology On Healthcare And The Difficulties Of Integration, Skyler J. Pavlish-Carpenter

Honors Undergraduate Theses

Background: Disruptive technology describes technology that is significantly more advanced than previous iterations, such as: 3D printing, genetic manipulation, stem cell research, innovative surgical procedures, and computer-based charting software. These technologies often require extensive overhauls to implement into older systems and must overcome many difficult financial and societal complications before they can be widely used. In a field like healthcare that makes frequent advancements, these difficulties can mean that the technology will not be utilized to its full potential or implemented at all.

Objective: To determine the inhibiting factors that prevent disruptive technology from being implemented in conventional healthcare.

Methods: …

Universal Swine Influenza Antigen And Vaccine, Zhao Wang

Electronic Theses and Dissertations

Swine influenza A viruses pose a serious concern for global health and worldwide swine industry considering their evasion from vaccine-induced immune responses. Formulation of effective influenza vaccines can be complicated by both antigenic shift to a different subtype of hemagglutinin (HAs) and antigenic drift within a particular HA subtype. To address these concerns, we employed a systematic approach to determine the antigenic determinants of swine influenza A viruses by focusing on H1 and H3 subtypes. In parallel, we used a cross-disciplinary approach including structural biology and modeling, virology, and immunology to identify swine influenza A virus-derived HA fusion intermediates broadly …

Synthetic Investigation Of Natural Products Causing Dopaminergic Neurodegeneration, Michael John Cunningham

Electronic Theses and Dissertations

The terrestrial organisms Streptomyces venezuelae and Rhaponticum repens produce toxic secondary metabolites that likely function as chemical deterrents. The polyketide SV-6 from S. venezuelae and the sesquiterpene lactone repin from R. repens both produce dose-dependent and selective degeneration of dopaminergic neurons. These molecules represent two possible tools that can be used to explore chemotoxic induction of Parkinson’s disease. In the case of SV-6, a newly isolated metabolite, total synthesis was undertaken to confirm its structure and biological activity. The natural product was produced from methacrolein and Roche ester starting materials that were elaborated to their respective fragments, a vinyl iodide …

Hyperthermia As A Cancer Treatment- From Theory To Practice, Graham Fullerton

CMC Senior Theses

Using iron super-paramagnetic and ferromagnetic nanoparticles composed of Fe₃O₄ molecules, scientists analyze the effectiveness and practicality of this new treatment theory, hyperthermia. The problems of magnetic particle density, isothermal barriers/cellular cooling thresholds, and nanoparticle specific targeting are addressed in this review.

Iron magnetic nanoparticles were chosen due to their relatively low biological reactivates and lack of subsequent cellular toxicity. However, there are significant heating problems associated with these magnetic nanoparticles due to their relative size and short thermal time constants or thermal half-lives. Effectively, these aforementioned issues create a phenomenon where cancerous cells, surrounded by unheated healthy …

Synthesis And Biological Evaluation Of Novel Drug Candidates To Address Drug Resistance In Tuberculosis And Fungal Diseases, Huy Ngo

Theses and Dissertations--Pharmacy

Tuberculosis (TB) and fungal infections are two of the most lethal infectious diseases worldwide due to the emergence of drug-resistant Mycobacterium tuberculosis (Mtb) and fungal strains that can resist the most potent antimicrobial drugs currently employed. Due to the rise of these drug resistant strains, effective treatment options for these two infections are limited. This dissertation aims at exploring novel drug scaffolds to help combat drug resistance in TB and fungal infections.

TB caused by the pathogenic Mtb is, alongside with human immunodeficiency virus acquired immunodeficiency virus (HIV), the deadliest infectious disease worldwide with approximately 2-3 billion people …

Comparative Study Of Growth Patterns In Seven Strains Of Japanese Quail Using Nonlinear Regression Modeling, Hadi Farajiarough, Mohammad Rokouei, Ali Maghsoudi, Mahmoud Ghazaghi

Turkish Journal of Veterinary & Animal Sciences

The aim of this study was to compare the growth pattern of seven strains of Japanese quail including Wild, Italian Speckled, Tuxedo, Scarlett, English white, White button, and A&M Texas by nonlinear growth functions including Gompertz, Richards, logistic, Lopez, and Weibull functions. The body weights of the unselected randomly bred populations of these strains were measured weekly from 1 to 42 days of age and then used to fit functions. The fitness of each function was assessed by statistics including the mean square error, Akaike information criterion, Bayesian information criterion, and adjusted coefficient of determination. The results showed that Gompertz …

Synthesis Of 1,4-Triazolyl Combretacoumarins As Potential Anticancer Agents, Tashrique A. Khandaker

Dissertations and Theses

Coumarins are natural compounds that have various physiological and therapeutic properties, making them pharmacologically important. Combretastatin A-4 (CA-4) is a microtubule-binding agent that has potent cytotoxic effects against human cell lines. In CA-4 the trimethoxyarene moiety plays a crucial role in its carcinopreventive effect. Thus, we decided to synthesize novel, potential anti-cancer agents called 1,4-triazolyl combretacoumarins, by coupling different coumarins and the functionally relevant group of CA-4 i.e, the trimethoxyarene moiety, via a 1,2,3-triazolyl ring using a copper-catalyzed [3 + 2] azide-alkyne cycloaddition (CuAAC) reaction, which is a very atom-economical reaction. The coupling partners, 4-azidocoumarins, required for making these …

Investigating The Molecular Pathology Of Dupuytren’S Disease, Robert Pearce

Theses

The eponymous progressive palmar fibromatosis described by Guillaume Dupuytren in 1831 is a common and debilitating disease with limited treatment options and high rates of recurrence after intervention. Dupuytren’s disease has been generally accepted as predominantly affecting Northern European individuals; Dupuytren’s disease is sometimes referred to as “Vikings Disease” as an attribution to this ethnic origin. Its familial occurrence in all communities is suggestive of Mendelian inheritance as an autosomal dominant disease with incomplete penetrance. The genetic and molecular basis of Dupuytren’s disease (DD) has been the focus of many studies, with increasingly sophisticated approaches since the sequencing of the …

Chlamydia Pneumoniae: An Etiologic Agent For Late-Onset Dementia, Brian J. Balin Phd, Christine Hammond, Christopher S. Little, Susan Hingley, Zein Al-Atrache, Denah Appelt, Judith A Whittum-Hudson, Alan P Hudson

PCOM Scholarly Works

The disease known as late-onset Alzheimer's disease is a neurodegenerative condition recognized as the single most common form of senile dementia. The condition is sporadic and has been attributed to neuronal damage and loss, both of which have been linked to the accumulation of protein deposits in the brain. Significant progress has been made over the past two decades regarding our overall understanding of the apparently pathogenic entities that arise in the affected brain, both for early-onset disease, which constitutes approximately 5% of all cases, as well as late-onset disease, which constitutes the remainder of cases. Observable neuropathology includes: neurofibrillary …

Ischemic Stroke Is Associated With The Pro-Inflammatory Potential Of N-Glycosylated Immunoglobulin G, Di Liu, Zhongyao Zhao, Anxin Wang, Siqi Ge, Hao Wang, Xiaoyu Zhang, Qi Sun, Weijie Cao, Ming Sun, Lijuan Wu, Manshu Song, Yong Zhou, Wei Wang, Youxin Wang

Research outputs 2014 to 2021

Background

Glycosylation significantly affects protein structure and function and thus participates in multiple physiologic and pathologic processes. Studies demonstrated that immunoglobulin G (IgG) N-glycosylation associates with the risk factors of ischemic stroke (IS), such as aging, obesity, dyslipidemia, type 2 diabetes, and hypertension.

Methods

The study aimed to investigate the association between IgG N-glycosylation and IS in a Chinese population. IgG glycome composition in patients with IS (n = 78) and cerebral arterial stenosis (CAS) (n = 75) and controls (n = 77) were analyzed by ultra-performance liquid chromatography.

Results

Eleven initial glycans and 10 …

Research News. Publications, 2017. Volume 2, University Of Mississippi. School Of Pharmacy, Soumyajit Majumdar

Publications (2015-)

Publications that appeared during the period July 1 through December 31, 2017

Ependymomas Overexpress Chemoresistance And Dna Repairrelated Proteins, Sherise D. Ferguson, Shouhao Zhou, Joanne Xiu, Yuuri Hashimoto, Nader Sanai, Lyndon Kim, Santosh Kesari, John De Groot, David Spetzler, Amy B. Heimberger

Department of Neurosurgery Faculty Papers

Background: After surgery and radiation, treatment options for ependymoma are few making recurrence a challenging issue. Specifically, the efficacy of chemotherapy at recurrence is limited. We performed molecular profiling on a cohort of ependymoma cases in order to uncover therapeutic targets and to elucidate the molecular mechanisms contributing to treatment resistance. Results: This ependymoma cohort showed minimal alterations in gene amplifications and mutations but had high expression rates of DNA synthesis and repair enzymes such as RRM1 (47%), ERCC1 (48%), TOPO1 (62%) and class III β-tublin (TUBB3) (57%), which are also all associated with chemoresistance. This cohort also had high …

Cxc Chemokines Exhibit Bactericidal Activity Against Multidrug-Resistant Gram-Negative Pathogens, Erum Khan, Matthew A. Crawford, Debra J. Fisher, Lisa M. Leung, Sara Lomonaco, Christine Lascols, Antonio Cannatelli,, Gian Maria Rossolini, Yohei Doi, David R. Goodlett

Department of Pathology and Laboratory Medicine

The continued rise and spread of antimicrobial resistance among bacterial pathogens pose a serious challenge to global health. Countering antimicrobial-resistant pathogens requires a multifaceted effort that includes the discovery of novel therapeutic approaches. Here, we establish the capacity of the human CXC chemokines CXCL9 and CXCL10 to kill multidrug-resistant Gram-negative bacteria, including New Delhi metallo-beta-lactamase-1-producing Klebsiella pneumoniae and colistin-resistant members of the family Enterobacteriaceae that harbor the mobile colistin resistance protein MCR-1 and thus possess phosphoethanolamine-modified lipid A. Colistin-resistant K. pneumoniae isolates affected by genetic mutation of the PmrA/PmrB two-component system, a chromosomally encoded regulator of lipopolysaccharide modification, and containing …

Developing Algorithms For Quantifying The Super Resolution Microscopic Data: Applications To The Quantification Of Protein-Reorganization In Bacteria Responding To Treatment By Silver Ions, Sai Divya Challapalli

Graduate Theses and Dissertations

Histone-like nucleoid structuring proteins (HNS) play significant roles in shaping the chromosomal DNA, regulation of transcriptional networks in microbes, as well as bacterial responses to environmental changes such as temperature fluctuations. In this work, the intracellular organization of HNS proteins in E. coli bacteria was investigated utilizing super-resolution fluorescence microscopy, which surpasses conventional microscopy by 10–20 fold in spatial resolution. More importantly, the changes of the spatial distribution of HNS proteins in E. coli, by addition of silver ions into the growth medium were explored. To quantify the spatial distribution of HNS in bacteria and its changes, an automatic method …