Digital Commons Network^™

Dissecting The Mechanisms Of Venetoclax Resistance In Myelodysplastic Syndromes, Shuaitong Chen

Dissertations and Theses (Open Access)

Myelodysplastic syndromes (MDS) are a class of heterogeneous clonal hematopoietic disorders. The current standard of care for MDS is the hypomethylating agent (HMA)-based therapy. However, only 50 percent of the patients respond, with transient effects and no approved second-line treatment options after their diseases progress to acute myeloid leukemia (AML). The mechanisms that govern HMA failure are unknown. Recently, we unveiled that MDS are maintained and propagated by two different immunophenotypically distinct hierarchical cellular organizations of MDS hematopoietic stem and progenitor cells (HSPCs) through the upregulation of specific survival pathways. This finding allowed us to potentially stratify MDS patients into …

A Tale Of Itam Tails: New Insights Into The Molecular Mechanisms That Tune Fcɛri Signaling, William K. Kanagy

Biomedical Sciences ETDs

Immunoreceptor Tyrosine-based Activating Motif (ITAM) receptors are critical in sensing extracellular antigen and initiating an immune response. The ITAM receptor FcɛRI, termed the high affinity IgE receptor, is the primary promoter of inducing the Type 1 allergic response and is primarily expressed in mast cells and basophils. In this dissertation, I worked to determine how early signaling events initiated at the FcɛRI ITAM interface tune downstream signaling outcomes. I began by determining that differential phospho-tyrosine ITAM patterns produce unique recruitment profiles of the accessory kinases proteins Syk and Lyn. I next determined the differential signaling ITAM capabilities of Lyn and …

Thanatechnology And The Living Dead: New Concepts In Digital Transformation And Human-Computer Interaction, Vural Özdemir, Simon Springer, Arif Ylldlrlm, Sehmus Biçer, Asllgül Kendirci, Semra Sardaş, Hakan Klllç, Nezih Hekim, Tanja Kunej, Kazlm Yalçln Arga, Kevin Dzobo, Wei Wang, Marius Geanta, Angela Brand, Mustafa Bayram

Research outputs 2014 to 2021

In a digital society, shall we be the authors of our own experience, not only during our lifetime but also after we die? We ask this question because dying and bereavement have become even harder, and much less private, in the digital age. New big data-driven digital industries and technologies are on the rise, with promises of interactive 3D avatars and storage of digital memories of the deceased, so they can continue to exist online as the "living dead"in a digital afterlife. Famous rock and roll icons like Roy Orbison, Frank Zappa, Ronnie James Dio, and Amy Winehouse have famously …

Contemporary Challenges And Opportunities For The Management Of Bird Damage At Field Crop Establishment, Christophe Sausse, Alice Baux, Michel Bertrand, Elsa Bonnaud, Sonia Canavelli, Alexandra Destrez, Page E. Klug, Lourdes Olivera, Ethel Rodriguez, Guilllermo Tellechea, Sebastian Zuil

United States Department of Agriculture Wildlife Services: Staff Publications

Bird damage, from sowing to crop establishment, is an important issue for farmers in many parts of the world. However, reliable and cost-effective solutions remain elusive because management tools and research on the subject are limited. The spatial variability of damage across landscapes and the adaptative behaviour of birds create further challenges. Additionally, the issue must be tackled at the landscape scale and involve a variety of stakeholders with conflicting interests and objectives. We summarize some of the challenges and opportunities identified to face these difficulties and address four major research directions for operational solutions including 1) crop damage assessment, …

Evaluation Of Somatic Mutations In Solid Metastatic Pan-Cancer Patients, Moom Roosan, Isa Mambetsariev, Rebecca Pharaon, Jeremy Fricke, Angel R. Baroz, Joseph Chao, Chen Chen, Mohd W. Nasser, Ramakanth Chirravuri-Venkata, Maneesh Jain, Lynette Smith, Susan E. Yost, Karen L. Reckamp, Raju Pillai, Leonidas Arvanitis, Michelle Afkhami, Edward W. Wang, Vincent Chung, Mihaela Cristea, Marwan Fakih, Marianna Koczywas, Erminia Massarelli, Joanne Mortimer, Yuan Yuan, Surinder K. Batra, Sumanta Pal, Ravi Salgia

Pharmacy Faculty Articles and Research

Metastasis continues to be the primary cause of all cancer-related deaths despite the recent advancements in cancer treatments. To evaluate the role of mutations in overall survival (OS) and treatment outcomes, we analyzed 957 metastatic patients with seven major cancer types who had available molecular testing results with a FoundationOne CDx^® panel. The most prevalent genes with somatic mutations were TP53, KRAS, APC, and LRP1B. In this analysis, these genes had mutation frequencies higher than in publicly available datasets. We identified that the somatic mutations were seven mutually exclusive gene pairs and an additional fifty-two co-occurring gene pairs. Mutations …

Esomeprazole Attenuates Inflammatory And Fibrotic Response In Lung Cells Through The Mapk/Nrf2/Ho1 Pathway, Afshin Ebrahimpour, Min Wang, Li Li, Anil G Jegga, Mark D Bonnen, N Tony Eissa, Ganesh Raghu, Soma Jyothula, Farrah Kheradmand, Nicola A Hanania, Ivan O Rosas, Yohannes T Ghebre

Faculty, Staff and Students Publications

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is an orphan disease characterized by progressive loss of lung function resulting in shortness of breath and often death within 3-4 years of diagnosis. Repetitive lung injury in susceptible individuals is believed to promote chronic oxidative stress, inflammation, and uncontrolled collagen deposition. Several preclinical and retrospective clinical studies in IPF have reported beneficial outcomes associated with the use of proton pump inhibitors (PPIs) such as esomeprazole. Accordingly, we sought to investigate molecular mechanism(s) by which PPIs favorably regulate the disease process.

METHODS: We stimulated oxidative stress, pro-inflammatory and profibrotic phenotypes in primary human lung epithelial …

Advancing The Preclinical Development Of Secondary Metabolites From Cacospongia Mycofijiensis For The Treatment Of Cancer, Joseph Morris

Natural Sciences and Mathematics | Biological Sciences Master's Theses

The marine sponge Cacospongia mycofijiensis from the Indo-Pacific has proven to be a source of structurally diverse secondary metabolites that are biologically active against a variety of distinct targets. Current interest in the secondary metabolites of C. mycofijiensis largely stems from a) their potent and preferential cytotoxicity for cancer cell lines versus normal cells, making many of them promising leads as cancer therapeutics and b) the novel mechanisms of action responsible for their impressive cytotoxicity. However, limited compound availability has resulted in a paucity of studies aimed at advancing the preclinical development of these secondary metabolites from C. mycofijiensis for …

Investigation Of Alpl Variant States And Clinical Outcomes: An Analysis Of Adults And Adolescents With Hypophosphatasia Treated With Asfotase Alfa., Priya S. Kishnani, Guillermo Del Angel, Shanggen Zhou, Eric T. Rush

Manuscripts, Articles, Book Chapters and Other Papers

Background: Hypophosphatasia (HPP), a rare metabolic disease, can be inherited in an autosomal recessive (biallelic) or an autosomal dominant (monoallelic) manner. Most of the severe, early-onset, frequently lethal HPP in infants is acquired through recessive inheritance; less severe, later-onset, typically nonlethal HPP phenotypes are acquired through either dominant or recessive inheritance. HPP's variable clinical presentation arises from >400 identified ALPL pathogenic variants with likely variable penetrance, especially with autosomal dominant inheritance. This post hoc analysis investigated the relationship between ALPL variant state (biallelic and monoallelic) and clinical outcomes with asfotase alfa in HPP.

Methods: Data were pooled from two phase …

Vitamin B12 Deficiency Does Not Stimulate Amyloid-Beta Toxicity In A Ceanorhabditis Elegans Model Of Alzheimer’S Disease, Opeyemi F. Showemimo

Electronic Theses and Dissertations

Alzheimer’s disease (AD) is symptomized by amyloid-beta plaques in the brain and accounts for more than 65 percent of dementia cases. Vitamin B12 (cobalamin) deficiency can result in similar cognitive impairment and roughly 15% of the elderly are vitamin B12 deficient. Vitamin B12 deficiency results in the accumulation of toxic methylmalonic acid and homocysteine. Hyperhomocysteinemia is a strong risk factor for AD. To test if vitamin B12 deficiency stimulates amyloid-beta toxicity, Caenorhabditis elegans expressing amyloid-beta in muscle were fed either vitamin B12-deficient OP50-1 or vitamin B12-rich HT115(DE3) E. coli bacteria. Increased amyloid-beta toxicity was found in worms fed the …

Herbal Extracts As Neuroprotective Agents In An In-Vitro Model Of Aluminum Neurotoxicity, Nada Ezzelarab

Theses and Dissertations

Background: Aluminum toxicity due to environmental or industrial exposure, medical applications, or from cooking utensils is a serious medical problem. The current study aims to investigate three herbal extracts: pomegranate peel extract, Achillea fragrantissima extract, and papaya fruit extract to combat this neurotoxicity.

Methods: Chemical characterization of the three extracts were evaluated using HPLC MS while their neuroprotective activity was assayed using MTT assay on SHSY5Y cells and nitric oxide levels.

Results: Using HPLC-MS chromatography, we have identified twenty-one compounds in the hydro-alcoholic Achillea fragrantissima, seventeen were determined in the pomegranate peel, eleven were assessed in the Carica papaya …

Structure, Function And Inhibition Of Critical Protein-Protein Interactions Involving Mixed Lineage Leukemia 1 And Its Fusion Oncoproteins, Xin Li, Yongcheng Song

Faculty, Staff and Students Publications

Mixed lineage leukemia 1 (MLL1, also known as MLL or KMT2A) is an important transcription factor and histone-H3 lysine-4 (H3K4) methyltransferase. It is a master regulator for transcription of important genes (e.g., Hox genes) for embryonic development and hematopoiesis. However, it is largely dispensable in matured cells. Dysregulation of MLL1 leads to overexpression of certain Hox genes and eventually leukemia initiation. Chromosome translocations involving MLL1 cause ~ 75% of acute leukemia in infants and 5-10% in children and adults with a poor prognosis. Targeted therapeutics against oncogenic fusion MLL1 (onco-MLL1) are therefore needed. Onco-MLL1 consists of the N-terminal DNA-interacting domains …

High-Performance Thin-Layer Chromatography For Rutin, Chlorogenic Acid, Caffeic Acid, Ursolic Acid, And Stigmasterol Analysis In Periploca Aphylla Extracts, Raha Orfali, Shagufta Perveen, Hanan Y. Aati, Perwez Alam

Faculty and Student Publications

Periploca aphylla (PA), an interesting Saudi medicinal plant, is used in folk medicine to treat urticaria, cerebral fever, tumors, and swelling. To prove its use in folk medicine, two different extracts from the aerial parts of the plant: chloroform P-1, and n-butanol P-2 were subjected to biological assays to screen peroxisome proliferator-activated receptors (PPARα and PPARγ) agnostic, antiinflammatory, antioxidant, cytotoxic, and estrogenic activities. In addition, five bioactive secondary metabolites were isolated from the aerial parts of the plant: rutin, chlorogenic acid, caffeic acid, ursolic acid, and stigmasterol. P-1 and P-2 decreased cellular oxidative stress by 47.0% and 62.0%, respectively, compared …

Classification Of Molecular Subtypes Of High-Grade Serous Ovarian Cancer By Maldi-Imaging., Wanja Kassuhn, Oliver Klein, Silvia Darb-Esfahani, Hedwig Lammert, Sylwia Handzik, Eliane T Taube, Wolfgang D Schmitt, Carlotta Keunecke, David Horst, Felix Dreher, Joshy George, David D Bowtell, Oliver Dorigo, Michael Hummel, Jalid Sehouli, Nils Blüthgen, Hagen Kulbe, Elena I Braicu

Faculty Research 2021

Despite the correlation of clinical outcome and molecular subtypes of high-grade serous ovarian cancer (HGSOC), contemporary gene expression signatures have not been implemented in clinical practice to stratify patients for targeted therapy. Hence, we aimed to examine the potential of unsupervised matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS) to stratify patients who might benefit from targeted therapeutic strategies. Molecular subtyping of paraffin-embedded tissue samples from 279 HGSOC patients was performed by NanoString analysis (ground truth labeling). Next, we applied MALDI-IMS paired with machine-learning algorithms to identify distinct mass profiles on the same paraffin-embedded tissue sections and distinguish HGSOC subtypes by …

Discovery And Characterization Of Bromodomain 2-Specific Inhibitors Of Brdt, Zhifeng Yu, Angela F Ku, Justin L Anglin, Rajesh Sharma, Melek Nihan Ucisik, John C Faver, Feng Li, Pranavanand Nyshadham, Nicholas Simmons, Kiran L Sharma, Sureshbabu Nagarajan, Kevin Riehle, Gundeep Kaur, Banumathi Sankaran, Marta Storl-Desmond, Stephen S Palmer, Damian W Young, Choel Kim, Martin M Matzuk

Faculty, Staff and Students Publications

Bromodomain testis (BRDT), a member of the bromodomain and extraterminal (BET) subfamily that includes the cancer targets BRD2, BRD3, and BRD4, is a validated contraceptive target. All BET subfamily members have two tandem bromodomains (BD1 and BD2). Knockout mice lacking BRDT-BD1 or both bromodomains are infertile. Treatment of mice with JQ1, a BET BD1/BD2 nonselective inhibitor with the highest affinity for BRD4, disrupts spermatogenesis and reduces sperm number and motility. To assess the contribution of each BRDT bromodomain, we screened our collection of DNA-encoded chemical libraries for BRDT-BD1 and BRDT-BD2 binders. High-enrichment hits were identified and resynthesized off-DNA and examined …

Inhibition Of Camkk2 Impairs Autophagy And Castration-Resistant Prostate Cancer Via Suppression Of Ampk-Ulk1 Signaling, Chenchu Lin, Alicia M Blessing, Thomas L Pulliam, Yan Shi, Sandi R Wilkenfeld, Jenny J Han, Mollianne M Murray, Alexander H Pham, Kevin Duong, Sonja N Brun, Reuben J Shaw, Michael M Ittmann, Daniel E Frigo

Faculty, Staff and Students Publications

Previous work has suggested androgen receptor (AR) signaling mediates prostate cancer progression in part through the modulation of autophagy. However, clinical trials testing autophagy inhibition using chloroquine derivatives in men with castration-resistant prostate cancer (CRPC) have yet to yield promising results, potentially due to the side effects of this class of compounds. We hypothesized that identification of the upstream activators of autophagy in prostate cancer could highlight alternative, context-dependent targets for blocking this important cellular process during disease progression. Here, we used molecular, genetic and pharmacological approaches to elucidate an AR-mediated autophagy cascade involving Ca2+/calmodulin-dependent protein kinase kinase 2 (CAMKK2; …

Tools For Visualizing And Analyzing Fourier Space Sampling In Cryo-Em, Philip R Baldwin, Dmitry Lyumkis

Faculty, Staff and Students Publications

A complete understanding of how an orientation distribution contributes to a cryo-EM reconstruction remains lacking. It is necessary to begin critically assessing the set of views to gain an understanding of its effect on experimental reconstructions. Toward that end, we recently suggested that the type of orientation distribution may alter resolution measures in a systematic manner. We introduced the sampling compensation factor (SCF), which incorporates how the collection geometry might change the spectral signal-to-noise ratio (SSNR), irrespective of the other experimental aspects. We show here that knowledge of the sampling restricted to spherical surfaces of sufficiently large radii in Fourier …

Transcriptomic Profiling Of Fibropapillomatosis In Green Sea Turtles (Chelonia Mydas) From South Texas, Nicholas B. Blackburn, Ana C. Leandro, Nina Nahvi, Mariana A. Devlin, Marcelo Leandro, Ignacio Martinez Escobedo, Juan M. Peralta, Jeff George, Thomas W. Demaar, John Blangero, Megan Keniry, Joanne E. Curran

School of Medicine Publications

Sea turtle fibropapillomatosis (FP) is a tumor promoting disease that is one of several threats globally to endangered sea turtle populations. The prevalence of FP is highest in green sea turtle (Chelonia mydas) populations, and historically has shown considerable temporal growth. FP tumors can significantly affect the ability of turtles to forage for food and avoid predation and can grow to debilitating sizes. In the current study, based in South Texas, we have applied transcriptome sequencing to FP tumors and healthy control tissue to study the gene expression profiles of FP. By identifying differentially expressed turtle genes in …

Bone Microenvironmental Control Of Skeletal Malignancy, Chen Hao Lo

USF Tampa Graduate Theses and Dissertations

Bone is a common site of metastasis for many solid malignancies. Bone-metastatic cancers pose a significant clinical problem worldwide and is among the main causes for cancer patient morbidity and mortality. Patients with advanced bone-metastatic diseases often present with either osteolytic or osteogenic bone diseases as their cancers progress. These bone pathologies are products of the cancer co-opting the local bone remodeling stroma to yield important growth nutrients and factors. Unfortunately, skeletal metastases remain incurable and are fatal. Identifying and understanding the causal multicellular and molecular interactions underlying skeletal malignancies can yield crucial ideas for targeting and inhibiting disease progression. …

Robust Inference Of Kinase Activity Using Functional Networks, Serhan Yılmaz, Daniela M. Schlatzer, Mark R. Chance, Mehmet Koyutürk

Faculty Scholarship

Mass spectrometry enables high-throughput screening of phosphoproteins across a broad range of biological contexts. When complemented by computational algorithms, phospho-proteomic data allows the inference of kinase activity, facilitating the identification of dysregulated kinases in various diseases including cancer, Alzheimer’s disease and Parkinson’s disease. To enhance the reliability of kinase activity inference, we present a network-based framework, RoKAI, that integrates various sources of functional information to capture coordinated changes in signaling. Through computational experiments, we show that phosphorylation of sites in the functional neighborhood of a kinase are significantly predictive of its activity. The incorporation of this knowledge in RoKAI consistently …

Characterization And Localization Of Antigens For Serodiagnosis Of Human Paragonimiasis, Kurt C Curtis, Kerstin Fischer, Young-Jun Choi, Makedonka Mitreva, Gary J Weil, Peter U Fischer

2020-Current year OA Pubs

Paragonimiasis is a foodborne trematode infection that affects 23 million people, mainly in Asia. Lung fluke infections lead frequently to chronic cough with fever and hemoptysis, and are often confused with lung cancer or tuberculosis. Paragonimiasis can be efficiently treated with praziquantel, but diagnosis is often delayed, and patients are frequently treated for other conditions. To improve diagnosis, we selected five Paragonimus kellicotti proteins based on transcriptional abundance, recognition by patient sera, and conservation among trematodes and expressed them as His-fusion proteins in Escherichia coli. Sequences for these proteins have 76-99% identity with amino acid sequences for orthologs in the …

Biomedical Applications Of Vibrational Spectroscopy: Oral Cancer Diagnostics, Hugh Byrne, Isha Behl, Genecy Calado, Ola Ibrahim, M. Toner, Sheila Galvin, Claire M. Healy, Steven Flint, Fiona Lyng

Articles

Vibrational spectroscopy, based on either infrared absorption or Raman scattering, has attracted increasing attention for biomedical applications. Proof of concept explorations for diagnosis of oral potentially malignant disorders and cancer are reviewed, and recent advances critically appraised. Specific examples of applications of Raman microspectroscopy for analysis of histological, cytological and saliva samples are presented for illustrative purposes, and the future prospects, ultimately for routine, chairside in vivo screening are discussed.

Antecedents Of Borderline Personality Disorder And Antisocial Personality Disorder: An Examination Of Gene X Environment Interactions, Amy L. Medina

Dissertations, Theses, and Capstone Projects

Current thinking suggests that genotypes associated with impulse-control disorders and negative emotionality, such as monoamine oxidase-a (MAOA), interact with negative early environmental factors like childhood maltreatment and develop into the disorders know as Borderline Personality Disorder (BPD) and Antisocial Personality Disorder (ASPD). Using existing data from a prospective cohort design study of the consequences of child abuse and neglect, participants (N = 896 represent individuals with documented histories of child abuse and neglect and a matched comparison group that were followed up into adulthood and interviewed. A subsample of 631 participants gave permission for DNA extraction and analyses during …

A Timely Call To Arms: Covid-19, The Circadian Clock, And Critical Care, Jeffrey Haspel, Minjee Kim, Phyllis Zee, Tanja Schwarzmeier, Sara Montagnese, Satchidananda Panda, Adriana Albani, Martha Merrow

2020-Current year OA Pubs

We currently find ourselves in the midst of a global coronavirus disease 2019 (COVID-19) pandemic, caused by the highly infectious novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we discuss aspects of SARS-CoV-2 biology and pathology and how these might interact with the circadian clock of the host. We further focus on the severe manifestation of the illness, leading to hospitalization in an intensive care unit. The most common severe complications of COVID-19 relate to clock-regulated human physiology. We speculate on how the pandemic might be used to gain insights on the circadian clock but, more importantly, on …

A Peek Inside The Machines Of Bacterial Nucleotide Excision Repair, Thanyalak Kraithong, Silas Hartley, David Jeruzalmi, Danaya Pakotiprapha

Publications and Research

Double stranded DNA (dsDNA), the repository of genetic information in bacteria, archaea and eukaryotes, exhibits a surprising instability in the intracellular environment; this fragility is exacerbated by exogenous agents, such as ultraviolet radiation. To protect themselves against the severe consequences of DNA damage, cells have evolved at least six distinct DNA repair pathways. Here, we review recent key findings of studies aimed at understanding one of these pathways: bacterial nucleotide excision repair (NER). This pathway operates in two modes: a global genome repair (GGR) pathway and a pathway that closely interfaces with transcription by RNA polymerase called transcription-coupled repair (TCR). …

Isolation Of Catechins From Cycas Armstrongii Miq. Of An Egyptian Origin, Ahmed Ismail, Mohamed M. Radwan, Hossam M. Hassan, Abeer S. Moawad

Faculty and Student Publications

The phytochemical investigation of Cycas armstrongii Miq. leaves and twigs using different chromatographic techniques led to the isolation of three catechin monomers; catechin (1), epicatechin (2), and epigallocatechin-3-gallate (3), for the first time from this species. The chemotaxonomic significance of the isolated compounds is discussed in the rest of this article.

Developing A Targeted Ultrasound-Responsive Nanobubble-Based Gene Delivery System For Osteoporosis Treatment, Angela Shar

Honors Undergraduate Theses

The overall goal of this project was to develop, optimize, and test an ultrasound-responsive targeted nanobubble for delivering osteoporosis-related silencing genes such as Cathepsin K small interfering RNA (CTSK siRNA) for osteoporosis treatment. The nanobubbles were synthesized using an in situ sonochemical method. The nanobubble (NB) is composed of a gas core made from perfluorocarbon, stabilized with albumin, encapsulated with CTSK siRNA, and embedded with alendronate (AL) for bone targeting (CTSK siRNA-NB-AL). Following its development, the responsiveness of CTSK siRNA-NB-AL to a therapeutic ultrasound probe was examined. The results of biocompatibility tests with human bone marrow-derived mesenchymal stem cells proved …

Reframing A Curative To Preventative Culture, Gabriella Dacosta

Student Research Poster Presentations 2021

No abstract provided.

Exploring Efficacy Of An Anti-Malarial Nanomedicine In Non-Small Cell Lung Cancer Treatment, Vineela Parvathaneni

Theses and Dissertations

New drug and dosage form development faces significant challenges, especially in oncology, due to longer development cycle and associated scale-up complexities. Repurposing of existing drugs with potential anti-cancer activity into new therapeutic regimens provides a feasible alternative. In this project, amodiaquine (AQ), an anti-malarial drug, has been explored for its anti-cancer efficacy through formulating inhalable nanoparticulate systems using high-pressure homogenization (HPH) with scale-up feasibility and high reproducibility. A 32 multifactorial design was employed to better understand critical processes and formulation parameters so as to ensure product quality with improved anticancer efficacy in non-small cell lung cancer (NSCLC). Optimized AQ loaded …

Decreased Glucocerebrosidase Activity And Substrate Accumulation Of Glycosphingolipids In A Novel Gba1 D409v Knock-In Mouse Model., Nicole K Polinski, Terina N Martinez, Alexander Gorodinsky, Ralph Gareus, Michael Sasner, Mark Herberth, Robert Switzer, Syed O Ahmad, Mali Cosden, Monika Kandebo, Robert E Drolet, Peter D Buckett, Weisong Shan, Yi Chen, Lee J Pellegrino, Gregory D Ellsworth, Leo B Dungan, Warren D Hirst, Sean W Clark, Kuldip D Dave

Faculty Research 2021

Multiple mutations have been described in the human GBA1 gene, which encodes the lysosomal enzyme beta-glucocerebrosidase (GCase) that degrades glucosylceramide and is pivotal in glycosphingolipid substrate metabolism. Depletion of GCase, typically by homozygous mutations in GBA1, is linked to the lysosomal storage disorder Gaucher's disease (GD) and distinct or heterozygous mutations in GBA1 are associated with increased Parkinson's disease (PD) risk. While numerous genes have been linked to heritable PD, GBA1 mutations in aggregate are the single greatest risk factor for development of idiopathic PD. The importance of GCase in PD necessitates preclinical models in which to study GCase-related mechanisms …

Effect Of 5-O-(N-Boc-L-Alanine)-Renieramycin T In The Suppression Of Lung Cancer Stem Cells, Darinthip Suksamai

Chulalongkorn University Theses and Dissertations (Chula ETD)

Cancer stem cells (CSCs) drive aggressiveness and metastasis by utilizing stem cell-related signals. In this study, 5-O-(N-Boc-L-alanine)-renieramycin T (OBA-RT) was demonstrated to suppress CSC signals and induce apoptosis. OBA-RT exerted cytotoxic effects with a half-maximal inhibitory concentration of approximately 7 µM and mediated apoptosis as detected by annexin V/PI and nuclear staining assays. Mechanistically, OBA-RT exerted dual roles, activating p53-dependent apoptosis and concomitantly suppressing CSC signals. A p53-dependent pathway was indicated by the induction of p53 and the depletion of anti-apoptotic Mcl-1 and Bcl-2 proteins. Cleaved PARP was detected in OBA-RT-treated cells. Interestingly, OBA-RT exerted strong CSC-suppressing activity, reducing the …