Digital Commons Network^™

On A Sugar High: Role Of O-Glcnacylation In Cancer, Giang Le Minh, Emily M. Esquea, Riley G. Young, Jessie Huang, Mauricio J. Reginato

Kimmel Cancer Center Papers, Presentations, and Grand Rounds

Recent advances in the understanding of the molecular mechanisms underlying cancer progression have led to the development of novel therapeutic targeting strategies. Aberrant glycosylation patterns and their implication in cancer have gained increasing attention as potential targets due to the critical role of glycosylation in regulating tumor-specific pathways that contribute to cancer cell survival, proliferation, and progression. A special type of glycosylation that has been gaining momentum in cancer research is the modification of nuclear, cytoplasmic, and mitochondrial proteins, termed O-GlcNAcylation. This protein modification is catalyzed by an enzyme called O-GlcNAc transferase (OGT), which uses the final product of the …

Cancer Origin Tracing And Timing In Two High-Risk Prostate Cancers Using Multisample Whole Genome Analysis: Prospects For Personalized Medicine, Anssi Nurminen, Serafiina Jaatinen, Sinja Taavitsainen, Gunilla Högnäs, Tom Lesluyes, Naser Ansari-Pour, Teemu Tolonen, Kerstin Haase, Antti Koskenalho, Matti Kankainen, Juho Jasu, Hanna Rauhala, Jenni Kesäniemi, Tiia Nikupaavola, Paula Kujala, Irina Rinta-Kiikka, Jarno Riikonen, Antti Kaipia, Teemu Murtola, Teuvo L Tammela, Tapio Visakorpi, Matti Nykter, David C Wedge, Peter Van Loo, G Steven Bova

Faculty, Staff and Student Publications

BACKGROUND: Prostate cancer (PrCa) genomic heterogeneity causes resistance to therapies such as androgen deprivation. Such heterogeneity can be deciphered in the context of evolutionary principles, but current clinical trials do not include evolution as an essential feature. Whether or not analysis of genomic data in an evolutionary context in primary prostate cancer can provide unique added value in the research and clinical domains remains an open question.

METHODS: We used novel processing techniques to obtain whole genome data together with 3D anatomic and histomorphologic analysis in two men (GP5 and GP12) with high-risk PrCa undergoing radical prostatectomy. A total of …

Immune-Depleted Tumor Microenvironment Is Associated With Poor Outcomes And Btk Inhibitor Resistance In Mantle Cell Lymphoma, Preetesh Jain, Krystle Nomie, Nikita Kotlov, Vitaiy Segodin, Holly Hill, Chi Young Ok, Ahmed Fetooh, Rashmi Kanagal-Shamanna, Francisco Vega, Alexander Bagaev, Nathan Fowler, Christopher R Flowers, Michael Wang

Faculty, Staff and Student Publications

Mantle cell lymphoma (MCL) is a generally aggressive B cell non-Hodgkin lymphoma (B-NHL). Outcomes of patients have improved in the era of Bruton’s tyrosine kinase inhibitors (BTKi). However, MCL patients can develop resistance to BTKi over time and can progress [1]. Ibrutinib resistance in MCL is correlated with an overexpression of OXPHOS, MYC and PI3K/AKT/m-TOR pathways. Somatic mutations in TP53, KMT2D, NSD2, SMARCA4, CCND1, TRAF2, NFKBIE genes are reported with ibrutinib resistance [2]. A few reports have also demonstrated that a decrease in T cell numbers [3, 4] or a downregulation of effector/cytotoxic …

Activation Of Chaperone-Mediated Autophagy Inhibits The Aryl Hydrocarbon Receptor Function By Degrading This Receptor In Human Lung Epithelial Carcinoma A549 Cells, Rui Xiong, Dan Shao, Sandra Do, William K. Chan

Pacific Faculty Work

The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor and a substrate protein of a Cullin 4B E3 ligase complex responsible for diverse cellular processes. In the lung, this receptor is responsible for the bioactivation of benzo[a]pyrene during tumorigenesis. Realizing that the AHR function is affected by its expression level, we are interested in the degradation mechanism of AHR in the lung. Here, we have investigated the mechanism responsible for AHR degradation using human lung epithelial A549 cells. We have observed that the AHR protein levels increase in the presence of chloroquine (CQ), an autophagy inhibitor, in a dose-dependent …

Bola3 And Nfu1 Link Mitoribosome Iron–Sulfur Cluster Assembly To Multiple Mitochondrial Dysfunctions Syndrome, Hui Zhong, Alexandre Janer, Oleh Khalimonchuk, Hana Antonicka, Eric A. Shoubridge, Antoni Barrientos

Department of Biochemistry: Faculty Publications

The human mitochondrial ribosome contains three [2Fe–2S] clusters whose assembly pathway, role, and implications for mitochondrial and metabolic diseases are unknown. Here, structure-function correlation studies show that the clusters play a structural role during mitoribosome assembly. To uncover the assembly pathway, we have examined the effect of silencing the e xpression of Fe–S cluster biosynthetic and delivery factors on mitoribosome stability. We find that the mitoribosome receives its [²Fe–2S] clusters from the GLRX5-BOLA3 node. Additionally, the assembly of the small subunit depends on the mitoribosome biogenesis factor METTL17, recently reported containing a [⁴Fe–4S] cluster, which we …

Milk-Borne Small Extracellular Vesicles: Kinetics And Mechanisms Of Transport, Distribution, And Elimination, Alice Ngu, Javaria Munir, Janos Zempleni

Department of Nutrition and Health Sciences: Faculty Publications

Small extracellular vesicles (sEVs) in milk have the qualities desired for delivering therapeutics to diseased tissues. The production of bovine milk sEVs is scalable (10²¹ annually per cow), and they resist degradation in the gastrointestinal tract. Most cells studied to date internalize milk sEVs by a saturable process that follows Michaelis-Menten kinetics. The bioavailability of oral milk sEVs is approximately 50%. In addition to crossing the intestinal mucosa, milk sEVs also cross barriers such as the placenta and blood-brain barrier, thereby enabling the delivery of therapeutics to hard-to-reach tissues. In time course studies, levels of milk sEVs peaked in …

You Can’T Tell Mom Or Dad: What Is The Significance Of Family Post-Dobbs If Congress And The Federal Courts Do Not Recognize A Parent-Child Privilege?, Michael L. Fox, Mark D. Fox

Seton Hall Journal of Legislation and Public Policy

No abstract provided.

Next-Generation Crispr Gene-Drive Systems Using Cas12a Nuclease, Sara Sanz Juste, Emily M Okamoto, Christina Nguyen, Xuechun Feng, Víctor López Del Amo

Faculty, Staff and Student Publications

One method for reducing the impact of vector-borne diseases is through the use of CRISPR-based gene drives, which manipulate insect populations due to their ability to rapidly propagate desired genetic traits into a target population. However, all current gene drives employ a Cas9 nuclease that is constitutively active, impeding our control over their propagation abilities and limiting the generation of alternative gene drive arrangements. Yet, other nucleases such as the temperature sensitive Cas12a have not been explored for gene drive designs in insects. to address this, we herein present a proof-of-concept gene-drive system driven by Cas12a that can be regulated …

Vulnerability Of Elevation-Restricted Endemic Birds Of The Cordillera De Talamanca (Costa Rica And Panama) To Climate Change, Zhen Liu, Luis Sandoval, Lauren B. Sherman, Andrew M. Wilson

Neotropical Biodiversity

No abstract provided.

Widespread Dominance Of Methane Ebullition Over Diffusion In Freshwater Aquaculture Ponds, Renske J. E. Vroom, Sarian Kosten, Rafael M. Almeida, Raquel Mendonça, Ive S. Muzitano, Icaro Barbosa, Jonas Nasário, Ernandes S. Oliveira Junior, Alexander S. Flecker, Nathan Barros

School of Earth, Environmental, & Marine Sciences Faculty Publications

An ever-increasing demand for protein-rich food sources combined with dwindling wild fish stocks has caused the aquaculture sector to boom in the last two decades. Although fishponds are potentially strong emitters of the greenhouse gas methane (CH₄), little is known about the magnitude, pathways, and drivers of these emissions. We measured diffusive CH₄ emissions at the margin and in the center of 52 freshwater fishponds in Brazil. In a subset of ponds (n = 31) we additionally quantified ebullitive CH₄ fluxes and sampled water and sediment for biogeochemical analyses. Sediments (n = 20) were …

Pseudomonas Aeruginosa Kills Staphylococcus Aureus In A Polyphosphate-Dependent Manner, Ritika Sujit Shah

Theses and Dissertations

Due to their frequent coexistence in many polymicrobial infections, including in patients with wounds and cystic fibrosis, recent studies have started to investigate how the opportunistic pathogens Pseudomonas aeruginosa and Staphylococcus aureus interact with each other. P. aeruginosa rapidly outcompetes S. aureus under in vitro co-cultivation conditions, which is mediated by several of P. aeruginosa’s virulence factors. Here, we report that polyphosphate (polyP), an efficient stress defense system and virulence factor in P. aeruginosa, plays a role for the pathogen’s ability to inhibit and kill S. aureus in a contact-independent manner. We show that P. aeruginosa cells characterized by low …

Small Intestinal Polyp Burden In Pediatric Peutz-Jeghers Syndrome Assessed Through Capsule Endoscopy: A Longitudinal Study., Jeremy Stewart, Nathan R. Fleishman, Vincent S. Staggs, Mike Thomson, Nicole Stoecklein, Caitlin E. Lawson, Michael P. Washburn, Shahid Umar, Thomas M. Attard

Manuscripts, Articles, Book Chapters and Other Papers

The management of pediatric Peutz-Jeghers Syndrome (PJS) focuses on the prevention of intussusception complicating small intestinal (SI) polyposis. This hinges on the accurate appraisal of the polyp burden to tailor therapeutic interventions. Video Capsule Endoscopy (VCE) is an established tool to study SI polyps in children, but an in-depth characterization of polyp burden in this population is lacking. Methods: We performed a retrospective longitudinal cross-sectional analysis of VCE studies in pediatric PJS patients at our institution (CMKC) from 2010 to 2020. Demographic, clinical, and VCE findings reported by three reviewers in tandem were accrued. Polyp burden variables were modeled as …

Distinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation And Progression, Janine M. Deblasi

USF Tampa Graduate Theses and Dissertations

NRF2 is a redox-responsive transcription factor the directs the antioxidant program and several critical metabolic processes. Mutations in NRF2 or its negative regulator KEAP1 occur in up to one third of non-small cell lung cancers (NSCLCs) and are often associated with resistance to therapy and poor outcomes. In the present studies, murine alleles of the Keap1 and Nrf2 mutations found in human NSCLC were developed and I comprehensively investigated their impact on tumor initiation and progression. I observed that chronic Nrf2 stabilization by Keap1 loss-of-function or Nrf2 activating mutation was not sufficient to cause lung tumor initiation, even when p53 …

Complete Loss Of Tp53 And Rb1 Is Associated With Complex Genome And Low Immune Infiltrate In Pleomorphic Rhabdomyosarcoma, Hannah C Beird, Chia-Chin Wu, Michael Nakazawa, Davis Ingram, Joseph R Daniele, Rossana Lazcano, Latasha Little, Christopher Davies, Najat C Daw, Khalida Wani, Wei-Lien Wang, Xingzhi Song, Curtis Gumbs, Jianhua Zhang, Brian Rubin, Anthony Conley, Adrienne M Flanagan, Alexander J Lazar, P Andrew Futreal

Faculty, Staff and Student Publications

Rhabdomyosarcoma accounts for roughly 1% of adult sarcomas, with pleomorphic rhabdomyosarcoma (PRMS) as the most common subtype. Survival outcomes remain poor for patients with PRMS, and little is known about the molecular drivers of this disease. To better characterize PRMS, we performed a broad array of genomic and immunostaining analyses on 25 patient samples. In terms of gene expression and methylation, PRMS clustered more closely with other complex karyotype sarcomas than with pediatric alveolar and embryonal rhabdomyosarcoma. Immune infiltrate levels in PRMS were among the highest observed in multiple sarcoma types and contrasted with low levels in other rhabdomyosarcoma subtypes. …

Unleashing The Potential Of 1,3-Diketone Analogues As Selective Lh2 Inhibitors, Juhoon Lee, Hou-Fu Guo, Shike Wang, Yazdan Maghsoud, Erik Antonio Vázquez-Montelongo, Zhifeng Jing, Rae M Sammons, Eun Jeong Cho, Pengyu Ren, G Andrés Cisneros, Jonathan M Kurie, Kevin N Dalby

Faculty, Staff and Student Publications

Lysyl hydroxylase 2 (LH2) catalyzes the formation of highly stable hydroxylysine aldehyde-derived collagen cross-links (HLCCs), thus promoting lung cancer metastasis through its capacity to modulate specific types of collagen cross-links within the tumor stroma. Using 1 and 2 from our previous high-throughput screening (HTS) as lead probes, we prepared a series of 1,3-diketone analogues, 1-18, and identified 12 and 13 that inhibit LH2 with IC50's of approximately 300 and 500 nM, respectively. Compounds 12 and 13 demonstrate selectivity for LH2 over LH1 and LH3. Quantum mechanics/molecular mechanics (QM/MM) modeling indicates that the selectivity of 12 and 13 …

Kenyon Collegian - October 12, 2023

The Kenyon Collegian

No abstract provided.

Scoping Potential Routes To Uk Civil Unrest Via The Food System: Results Of A Structured Expert Elicitation, A Jones, S Bridle, K Denby, R Bhunoo, D Morton, L Stanborough, B Coupe, V Pilley, T Benton, P Faloon, T Matthews, C Pettinger

School of Health Professions

We report the results of a structured expert elicitation to identify the most likely types of potential food system disruption scenarios for the UK, focusing on routes to civil unrest. We take a backcasting approach by defining as an end-point a societal event in which 1 in 2000 people have been injured in the UK, which 40% of experts rated as “Possible (20–50%)”, “More likely than not (50–80%)” or “Very likely (>80%)” over the coming decade. Over a timeframe of 50 years, this increased to 80% of experts. The experts considered two food system scenarios and ranked their plausibility …

Learning And Gender In Everyday Life, Jocey Quinn

Plymouth Institute of Education

This paper focuses on the learning that happens in everyday life, beyond the formal learning environments of schools, colleges, and universities or even beyond community and adult education. It draws on posthuman concepts of ‘learning affect’ and ‘new worlds’ to conceptualise this as ‘invisible education’, affective and transformative, unrecognised but powerful and formative. Such invisible education has a powerful impact on formations of gender, class, race, sexuality, and disability and is thus a key field of enquiry with important consequences for gender equality. The paper will draw on a diverse range of grant funded qualitative, research projects to focus on …

Maxsim: Multi-Angle-Crossing Structured Illumination Microscopy With Height-Controlled Mirror For 3d Topological Mapping Of Live Cells, Pedro Felipe Gardeazabal Rodriguez, Yigal Lilach, Abhijit Ambegaonkar, Teresa Vitali, Haani Jafri, Hae Won Sohn, Matthew B. Dalva, Susan Pierce, Inhee Chung

Department of Neuroscience Faculty Papers

Mapping 3D plasma membrane topology in live cells can bring unprecedented insights into cell biology. Widefield-based super-resolution methods such as 3D-structured illumination microscopy (3D-SIM) can achieve twice the axial ( ~ 300 nm) and lateral ( ~ 100 nm) resolution of widefield microscopy in real time in live cells. However, twice-resolution enhancement cannot sufficiently visualize nanoscale fine structures of the plasma membrane. Axial interferometry methods including fluorescence light interference contrast microscopy and its derivatives (e.g., scanning angle interference microscopy) can determine nanoscale axial locations of proteins on and near the plasma membrane. Thus, by combining super-resolution lateral imaging of 2D-SIM …

Montana Kaimin, October 12, 2023, Students Of The University Of Montana, Missoula

Montana Kaimin, 1898-present

Student newspaper of the University of Montana, Missoula.

Perinatal Murine Cytomegalovirus Infection Reshapes The Transcriptional Profile And Functionality Of Nk Cells, Carmen Rožmanić, Eugene Park, Wayne M Yokoyama, Et Al.

2020-Current year OA Pubs

Infections in early life can elicit substantially different immune responses and pathogenesis than infections in adulthood. Here, we investigate the consequences of murine cytomegalovirus infection in newborn mice on NK cells. We show that infection severely compromised NK cell maturation and functionality in newborns. This effect was not due to compromised virus control. Inflammatory responses to infection dysregulated the expression of major transcription factors governing NK cell fate, such as Eomes, resulting in impaired NK cell function. Most prominently, NK cells from perinatally infected mice have a diminished ability to produce IFN-γ due to the downregulation of long non-coding RNA …

Widefield Imaging Of Rapid Pan-Cortical Voltage Dynamics With An Indicator Evolved For One-Photon Microscopy, Xiaoyu Lu, Yunmiao Wang, Zhuohe Liu, Yueyang Gou, Dieter Jaeger, François St-Pierre

Faculty, Staff and Students Publications

Widefield imaging with genetically encoded voltage indicators (GEVIs) is a promising approach for understanding the role of large cortical networks in the neural coding of behavior. However, the limited performance of current GEVIs restricts their deployment for single-trial imaging of rapid neuronal voltage dynamics. Here, we developed a high-throughput platform to screen for GEVIs that combine fast kinetics with high brightness, sensitivity, and photostability under widefield one-photon illumination. Rounds of directed evolution produced JEDI-1P, a green-emitting fluorescent indicator with enhanced performance across all metrics. Next, we optimized a neonatal intracerebroventricular delivery method to achieve cost-effective and wide-spread JEDI-1P expression in …

Anticancer Drug Screening Using Invitro Cell Proliferation Assay, Kristopher L. Ezell, Kyle Doxtater, Samantha Lopez, Sophia M. Leslie, Justin Wendel, Kamaldeep Paul, Vijay Lauxmi, Manish Tripathi

Research Colloquium

Introduction: In this presentation cell proliferation methods and how they are related to screening for effective chemotherapy drugs will be reviewed. Cancer in its most basic form is the unchecked mass dividing of cells while normal apoptosis is not undertaken for various reasons, some of which that have yet to be discovered. By these means’ tumors form that inhibit the functions of the organs it is residing in and the effected cells may metastasize and spread throughout the body. For this reason, chemotherapy drugs must be assessed through introduction into working strains of cultured cancer cells that are then screened …

Giving The Green Light To Red Light, Jackson Widlic

BUHealth

Emerging data suggests that light therapy offers a variety of health benefits. Absorption or reflection of light energy determines how light impacts the body. Different aspects of light exposure, including wavelength, duration, and intensity, can impact its ability to target human tissues. The longer the wavelength, the deeper it can penetrate the skin. Due to its long wavelength, red light therapy has been shown to improve sleep and enhance alertness by modulating hormone levels in the body. It has also shown benefit in those struggling with certain medical conditions, such as Parkinson’s Disease. Incorporating red light into a daily routine …

Honey: The Sweet Truth, Alex Szewczyk

BUHealth

Honey is a natural food that is packed with vitamins, minerals, enzymes, proteins, organic acids, and many other biologically active compounds. Its exact components may vary based on the unique collection of flowers and plants that honeybees pollinate. The nutrient dense quality of honey has different health benefits. People all around the world are currently suffering from chronic illnesses such as obesity, diabetes, hypertension, and dyslipidemia at unprecedented rates. When patients experience a combination of these disease states, it is known as metabolic syndrome (MetS). MetS is correlated with urbanization in developing countries, with sedentary lifestyle and poor diet as …

Resisting The Resistance: How The Environment Is Impacting Antibiotic Resistance, Hannah Hinrichs

BUHealth

Upon their discovery, antibiotics were known as “wonder drugs” due to their ability to cure serious bacterial infections. While antibiotics are still revolutionary in healthcare today, the emergence of antibiotic resistance is a growing threat to public health. Antibiotic resistance is simply a normal adaptive response where bacteria evolve over time. However, overuse of antibiotics, sub-optimal treatment regimens, and environmental exposures create optimal conditions for antibiotic resistance to develop and spread. Common ways antibiotics enter the environment are via wastewater and agricultural use. Even with properly functioning wastewater treatment systems, full removal of resistant bacteria may not be possible as …

A Natural Near-Infrared Fluorescent Probe For Cancer Cell Imaging, Benilde E. Adriano, Nycol M. Cotto, Neeraj Chauhan, Meena Jaggi, Subhash C. Chauhan, Murali M. Yallapu

Research Colloquium

Introduction: Near-Infrared (NIR) fluorescence-based imaging is a noteworthy and safer strategy for cancer cells/tissues imaging compared to radiological imaging. NIR fluorescence offers deep tissue penetration and have minimal obstruction by autofluorescence and photon scattering [1]. There are several NIR dyes including indocyanine green (ICG) [2] and IR-1061 [3] that allow high-resolution tissue imaging. However, these dyes possess some low-quality characteristics which limit their use, namely photo instability, toxicity, poor water solubility, and short half-lives [4]. Therefore, more efficient and effective alternatives are urgently required to provide the desired clinical outcomes. Chlorophyll (Chl) is a natural dietary NIR fluorescence emitting …

Development Of Targeted Drug Delivery System To Improve Immunotherapy In Pancreatic Cancer, Poornima Devi Shaji, Ana Martinez Bulnes, Nirnoy Dan, Subhash C. Chauhan, Sheema Khan, Murali M. Yallapu

Research Colloquium

Introduction: About 95% of tumor arises from epithelial cell lining ducts known to be pancreatic ductal adenocarcinomas, with less than 5-7% survival rate. Unfortunately, little progress has been seen in the outcomes of patients with PDAC as tumor develops high desmoplasia and chemo-resistance to chemotherapeutic drugs, such as gemcitabine (Gem). Immunotherapy has shown promising results in other cancers but limited response in pancreatic cancer due to desmoplasia and fibrotic tumor microenvironment. A recently identified mucin, MUC13 is aberrantly expressed in pancreatic tumors but not in normal pancreas. Due to its high membrane expression, MUC13 may serve as an excellent target …

Effects Of An Isotonic Medinilla Speciosa During And After Exercise, Nur Azis Rohmansyah, Fafa Nurdyansyah, Ashira Hiruntrakul, Mancharee Phumphitarkpanya

International Journal of Exercise Science

International Journal of Exercise Science 16(2): 1269-1283, 2023. Maintaining an adequate fluid balance is crucial during extended physical activity. It is currently unknown how drinking an isotonic medinilla speciosa beverage affects the autonomic regulation of heart function during and after exercise. The purpose of this study is to examine how drinking isotonic beverages affects heart rate variability (HRV) during and after intense exercise. A maximal exercise test to assess protocol loading, a control group, and an experimental group were all carried out by twenty-one young man (19.3 ± 1.2 years) over the course of three distinct protocols, with a 48-hour …

Emergentism Reconsidered, Kenji Lota

International Journal of Undergraduate Research and Creative Activities

This paper argues that emergentism is not committed to downward causation but of direct causation. Events that are believed to be caused by a mental state, whether physical or mental, are actually caused by a physical state with a mental property. These mental properties are caused by the complexity of a collection of several physical components. Emergentism, as a view, is often faced by the fallacy of composition given its nomological nature which leads one to resort to dualism. Mental properties cannot exist in and of itself, but it only supports the physical through entailment. Lastly, it gives a brief …