Digital Commons Network^™

The Effect Of Dexmedetomidine On The Mini-Cog Score And High-Mobility Group Box 1 Levels In Elderly Patients With Postoperative Neurocognitive Disorders Undergoing Orthopedic Surgery, Seung Hee Yoo, Mi Jin Jue, Yu-Hee Kim, Sooyoung Cho, Won-Joong Kim, Kye-Min Kim, Jong In Han, Heeseung Lee

Faculty and Staff Publications

Dexmedetomidine prevents postoperative cognitive dysfunction by inhibiting high-mobility group box 1 (HMGB1), which acts as an inflammatory marker. This study investigated the HMGB1 levels and the cognitive function using a Mini-Cog© score in elderly patients undergoing orthopedic surgery with dexmedetomidine infusion. In total, 128 patients aged ≥ 65 years were analyzed. The patients received saline in the control group and dexmedetomidine in the dexmedetomidine group until the end of surgery. Blood sampling and the Mini-Cog© test were performed before the surgery and on postoperative days 1 and 3. The primary outcomes were the effect of dexmedetomidine on the HMGB1 levels …

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 …

Novel Therapy Targeting Mutant-Krasg12d And Galectin-1 In Pancreatic Cancer, Ana I. Martinez Bulnes, Nirnoy Dan, Poornima Devi Shaji, Swathi Holla, Murali M. Yallapu, Sheema Khan

Research Colloquium

Introduction: Although, surgical resection and chemotherapy are the gold standard for treating Pancreatic Ductal Adenocarcinoma (PDAC), low patient survival rate remains the problem. The activating point mutation of the KRAS on codon-12 is present in 70–95% of PDAC cases and so far, no success has been achieved to inhibit KRAS. KRASG12D regulates cell proliferation, differentiation, apoptosis. Recent preliminary and published studies show high Galectin-1 (Gal-1) levels in both pancreatic cancer and stromal cells, which modulate tumor microenvironment and metastasis. Additionally, genetic deletion of gal1 inhibits metastasis and improves survival in KRAS mouse model of PDAC (1). Therefore, our objective is …

Molecular And Biochemical Analysis Of Cytochrome P450 2c19 And 2d6, Reema Saleous

Theses

Pharmacogenomics (PGx) is a relatively new field of study. It links genetics to pharmacology since it deals with the influence of the genetic makeup of the individual on their ability to respond to specific medications. Some of the most important genes in this field, dubbed very important pharmacogenes (VIPs), belong to the cytochrome P450 (CYP) superfamily of drug metabolizing enzymes. The two members of this family that are the main focus of this thesis are CYP2C19 and CYP2D6. They play major roles in the metabolism of numerous medications, and it is therefore imperative that variations within those genes in various …

Oral Dosages Of The Nsaid Aspirin Decreased The Growth Rate Of Species Found In The Human Gut Microbiome Including Akkermansia Muciniphila, Bacteroides Fragilis, Clostridium Sordellii, And Clostridium Difficile, Wyatt H. Greenbaum, Garrett J. Greenbaum, Anna Spiezio

PANDION: The Osprey Journal of Research and Ideas

Over past few decades, new insight has been revealed in the scientific community about the importance of the human gut microbiome relating to general health. It is known that imbalances in the species that reside in the human gut can cause organism-wide problems in humans. When prescribing or injecting oral medications, the thought of the downstream effects on the gut microbiome are not always considered. By exposing known healthy members of the gut; Akkermansia muciniphila, Bacteroides fragilis, Clostridium sordellii, and Clostridium difficile to the Aspirin, this study attempted to provide insight into the effects of the drug on bacterial growth. …

Evaluation Of Oxidative Status, Potassium, Magnesium, And Lipid Profile In Serum Of Patients With Β-Thalassemia Major, Thi-Qar, Iraq., Ahmed Jaber Ibrahim, Arwa H. M. Al–Saeed

Maaen Journal for Medical Sciences

Beta thalassemia major () is one of the more prevalent hereditary diseases in the globe due to a deficiency of globin chains. It is associated with lipid abnormalities, electrolytes, and oxidative stress that can lead to potentially fatal complications. The current study included 100 patients diagnosed with in an age group of 2-18 years compared to 80 healthy subjects. The current study included evaluating Complete blood count (CBC), iron status, lipid profile, potassium, and magnesium. Also, Oxidative status represented by Superoxide dismutase (SOD), Catalase (CAT), and Nitric oxide (NO) were investigated. The finding of this study included a significant increase …

Age- And Sex-Specific Reference Values Of Biventricular Flow Components And Kinetic Energy By 4d Flow Cardiovascular Magnetic Resonance In Healthy Subjects, Xiaodan Zhao, Ru-San Tan, Pankaj Garg, Ping Chai, Shuang Leng, Jennifer Ann Bryant, Lynette L S Teo, Tee Joo Yeo, Marielle V Fortier, Ting Ting Low, Ching Ching Ong, Shuo Zhang, Rob J Van Der Geest, John C Allen, Teng Hong Tan, James W Yip, Ju Le Tan, Marina Hughes, Sven Plein, Jos J M Westenberg, Liang Zhong

Student and Faculty Publications

BACKGROUND: Advances in four-dimensional flow cardiovascular magnetic resonance (4D flow CMR) have allowed quantification of left ventricular (LV) and right ventricular (RV) blood flow. We aimed to (1) investigate age and sex differences of 4D flow CMR-derived LV and RV relative flow components and kinetic energy (KE) parameters indexed to end-diastolic volume (KEi

METHODS: We performed 4D flow analysis in 163 healthy participants (42% female; mean age 43 ± 13 years) of a prospective registry study (NCT03217240) who were free of cardiovascular diseases. Relative flow components (direct flow, retained inflow, delayed ejection flow, residual volume) and multiple phasic KEi

RESULTS: …

Direct Modulators Of K-Ras-Membrane Interactions, Johannes Morstein, Rebika Shrestha, Que N Van, César A López, Neha Arora, Marco Tonelli, Hong Liang, De Chen, Yong Zhou, John F Hancock, Andrew G Stephen, Thomas J Turbyville, Kevan M Shokat

Student and Faculty Publications

Protein-membrane interactions (PMIs) are ubiquitous in cellular signaling. Initial steps of signal transduction cascades often rely on transient and dynamic interactions with the inner plasma membrane leaflet to populate and regulate signaling hotspots. Methods to target and modulate these interactions could yield attractive tool compounds and drug candidates. Here, we demonstrate that the conjugation of a medium-chain lipid tail to the covalent K-Ras(G12C) binder MRTX849 at a solvent-exposed site enables such direct modulation of PMIs. The conjugated lipid tail interacts with the tethered membrane and changes the relative membrane orientation and conformation of K-Ras(G12C), as shown by molecular dynamics (MD) …

Development Of A Sensitive Microplate Assay For Characterizing Rna Methyltransferase Activity: Implications For Epitranscriptomics And Drug Development, Isaiah K. Mensah, Allison B. Norvil, Ming He, Emma Lendy, Nicole Hjortland, Hern Tan, Richard T. Pomerantz, Andrew Mesecar, Humaira Gowher

Department of Biochemistry and Molecular Biology Faculty Papers

RNA methylation is a ubiquitous post-transcriptional modification found in diverse RNA classes and is a critical regulator of gene expression. In this study, we used Zika virus RNA methyltransferase (MTase) to develop a highly sensitive microplate assay that uses a biotinylated RNA substrate and radiolabeled AdoMet coenzyme. The assay is fast, highly reproducible, exhibits linear progress-curve kinetics under multiple turnover conditions, has high sensitivity in competitive inhibition assays, and significantly lower background levels compared with the currently used method. Using our newly developed microplate assay, we observed no significant difference in the catalytic constants of the full-length nonstructural protein 5 …

The Use Of Prognostic Markers To Predict Disease Progression And Clinical Outcome In Monoclonal Gammopathy Of Undetermined Significance, Smouldering Multiple Myeloma And Multiple Myeloma., Róisín C. Mcmonagle

International Undergraduate Journal of Health Sciences

Multiple Myeloma (MM) is an incurable plasma cell malignancy with a complex and incompletely understood molecular pathogenesis. Monoclonal Gammopathy of Undetermined Significance (MGUS) and Smouldering Multiple Myeloma (SMM) precede MM, with variable risks and rates of disease progression. The continuing high relapse and death rate in MM cases has prompted research into more accurate prognostic markers to predict progression from MGUS and SMM to MM, as well as identify MM cases with aggressive disease, in order to begin early, targeted and effective therapeutic intervention. Many studies have focused on utilising current markers more effectively, including M-protein, serum-free light chain ratio, …

The Circadian Nobiletin-Ror Axis Suppresses Adipogenic Differentiation And Iκbα/Nf-Κb Signaling In Adipocytes, Eunju Kim, Kazuaki Mawatari, Seung-Hee Yoo, Zheng Chen

Faculty and Staff Publications

Obesity is a known risk factor for metabolic diseases and is often associated with chronic inflammation in adipose tissue. We previously identified the polyethoxylated flavonoid Nobiletin (NOB) as a circadian clock modulator that directly binds to and activates the ROR receptors in the core oscillator, markedly improving metabolic fitness in obese mice. Here, we show that NOB enhanced the oscillation of core clock genes in differentiated 3T3-L1 adipocytes, including ROR target genes such as Bmal1, Cry1, Dec1, and Dec2. NOB inhibited lipid accumulation in 3T3-L1 and SVF cells, concomitant with the dysregulated circadian expression of adipogenic …

Effects Of Surface Treatment Method Forming New Nano/Micro Hierarchical Structures On Attachment And Proliferation Of Osteoblast-Like Cells, Jae-Seung Im, Hyunsuk Choi, Hyun-Wook An, Tae-Yub Kwon, Min-Ho Hong

Student and Faculty Publications

Titanium (Ti) and Ti-based alloys are commonly used in dental implants, and surface modifications of dental implants are important for achieving osseointegration (i.e., direct connection between the implant surface and bone). This study investigated the effect of an eco-friendly etching solution-a hydrogen peroxide-sodium bicarbonate mixture-on the surface properties and contact angles of osteoblast adhesion and proliferation on Ti surfaces. Disk-shaped Ti specimens were prepared using different surface treatments (machining, sandblasting, and sandblasting/acid-etching), and they were immersed in the etching solution and ultrasonically cleaned. Surface characterization was performed using scanning electron microscopy, digital microscopy, contact angle analysis, and X-ray photoelectron spectroscopy. …

Fan1 Removes Triplet Repeat Extrusions Via A Pcna- And Rfc-Dependent Mechanism, Ashutosh S. Phadte, Mayuri Bhatia, Hope Ebert, Haaris Abdullah, Essam Abed Elrazaq, Konstantin E. Komolov, Anna Pluciennik

Department of Biochemistry and Molecular Biology Faculty Papers

Human genome-wide association studies have identified FAN1 and several DNA mismatch repair (MMR) genes as modifiers of Huntington’s disease age of onset. In animal models, FAN1 prevents somatic expansion of CAG triplet repeats, whereas MMR proteins promote this process. To understand the molecular basis of these opposing effects, we evaluated FAN1 nuclease function on DNA extrahelical extrusions that represent key intermediates in triplet repeat expansion. Here, we describe a strand-directed, extrusion-provoked nuclease function of FAN1 that is activated by RFC, PCNA, and ATP at physiological ionic strength. Activation of FAN1 in this manner results in DNA cleavage in the vicinity …

Exogenous Exposure To Dihydroxyacetone Mimics High Fructose Induced Oxidative Stress And Mitochondrial Dysfunction, Raj Mehta

Honors Theses

Dihydroxyacetone (DHA) is a three-carbon sugar that is the active ingredient in sunless tanning products and a by-product of electronic cigarette (e-cigarette) combustion. Increased use of sunless tanning products and e-cigarettes has elevated exposures to DHA through inhalation and absorption. Studies have confirmed that DHA is rapidly absorbed into cells and can enter into metabolic pathways following phosphorylation to dihydroxyacetone phosphate (DHAP), a product of fructose metabolism. Recent reports have suggested metabolic imbalance and cellular stress results from DHA exposures. However, the impact of elevated exposure to DHA on human health is currently under-investigated. We propose that exogenous exposures to …

Targeting Mcl-1 By A Small Molecule Nsc260594 For Triple-Negative Breast Cancer Therapy, Shengli Dong, Margarite D. Matossian, Hassan Yousefi, Maninder Khosla, Bridgette M. Collins-Burow, Matthew E. Burow, Suresh K. Alahari

School of Graduate Studies Faculty Publications

Triple-negative breast cancers (TNBCs) are aggressive forms of breast cancer and tend to grow and spread more quickly than most other types of breast cancer. TNBCs can neither be targeted by hormonal therapies nor the antibody trastuzumab that targets the HER2 protein. There are urgent unmet medical needs to develop targeted drugs for TNBCs. We identified a small molecule NSC260594 from the NCI diversity set IV compound library. NSC260594 exhibited dramatic cytotoxicity in multiple TNBCs in a dose-and time-dependent manner. NSC260594 inhibited the Myeloid cell leukemia-1 (Mcl-1) expression through downregulation of Wnt signaling proteins. Consistent with this, NSC260594 treatment increased …

Src Stimulates Abl-Dependent Phosphorylation Of The Guanine Exchange Factor Net1a To Promote Its Cytosolic Localization And Cell Motility, Ashabari Sprenger, Heather S Carr, Arzu Ulu, Jeffrey A Frost

Student and Faculty Publications

The neuroepithelial cell transforming gene 1 (Net1) is a guanine nucleotide exchange factor for the small GTPase RhoA that promotes cancer cell motility and metastasis. Two isoforms of Net1 exist, Net1 and Net1A, both of which are sequestered in the nucleus in quiescent cells to prevent aberrant RhoA activation. Many cell motility stimuli drive cytosolic relocalization of Net1A, but mechanisms controlling this event are not fully understood. Here, we demonstrate that epithelial growth factor stimulates protein kinase Src- and Abl1-dependent phosphorylation of Net1A to promote its cytosolic localization. We show that Abl1 efficiently phosphorylates Net1A on Y373, and that phenylalanine …

Targeting Cgas/Sting Signaling-Mediated Myeloid Immune Cell Dysfunction In Time, Vijay Kumar, Caitlin Bauer, John H. Stewart

School of Graduate Studies Faculty Publications

Myeloid immune cells (MICs) are potent innate immune cells serving as first responders to invading pathogens and internal changes to cellular homeostasis. Cancer is a stage of altered cellular homeostasis that can originate in response to different pathogens, chemical carcinogens, and internal genetic/epigenetic changes. MICs express several pattern recognition receptors (PRRs) on their membranes, cytosol, and organelles, recognizing systemic, tissue, and organ-specific altered homeostasis. cGAS/STING signaling is a cytosolic PRR system for identifying cytosolic double-stranded DNA (dsDNA) in a sequence-independent but size-dependent manner. The longer the cytosolic dsDNA size, the stronger the cGAS/STING signaling activation with increased type 1 interferon …

Repair Of Noise-Induced Damage To Stereocilia F-Actin Cores Is Facilitated By Xirp2 And Its Novel Mechanosensor Domain, Elizabeth L Wagner, Jun-Sub Im, Stefano Sala, Maura I Nakahata, Terence E Imbery, Sihan Li, Daniel Chen, Katherine Nimchuk, Yael Noy, David W Archer, Wenhao Xu, George Hashisaki, Karen B Avraham, Patrick W Oakes, Jung-Bum Shin

Student and Faculty Publications

Prolonged exposure to loud noise has been shown to affect inner ear sensory hair cells in a variety of deleterious manners, including damaging the stereocilia core. The damaged sites can be visualized as 'gaps' in phalloidin staining of F-actin, and the enrichment of monomeric actin at these sites, along with an actin nucleator and crosslinker, suggests that localized remodeling occurs to repair the broken filaments. Herein, we show that gaps in mouse auditory hair cells are largely repaired within 1 week of traumatic noise exposure through the incorporation of newly synthesized actin. We provide evidence that Xin actin binding repeat …

Ca2+ Efflux Facilitated By Co-Transport Of Inorganic Phosphate Anion In The H+/Ca2+ Antiporter Yfke, Wei Niu, Wenchang Zhou, Shuo Lu, Trung Vu, Vasanthi Jayaraman, José D Faraldo-Gómez, Lei Zheng

Student and Faculty Publications

Ca2+ is an important signaling messenger. In microorganisms, fungi, and plants, H+/Ca2+ antiporters (CAX) are known to play key roles in the homeostasis of intracellular Ca2+ by catalyzing its efflux across the cell membrane. Here, we reveal that the bacterial CAX homolog YfkE transports Ca2+ in two distinct modes: a low-flux H+/Ca2+ exchange mode and a high-flux mode in which Ca2+ and phosphate ions are co-transported (1:1) in exchange for H+. Coupling with phosphate greatly accelerates the Ca2+ efflux activity of YfkE. Our studies reveal that Ca2+ and phosphate bind to adjacent sites in a central translocation pathway and lead …

Changes In Nascent Chromatin Structure Regulate Activation Of The Pro-Fibrotic Transcriptome And Myofibroblast Emergence In Organ Fibrosis, Morgan D. Basta, Svetlana Petruk, Ross Summer, Joel Rosenbloom, Peter J. Wermuth, Edward J. Macarak, Alex V. Levin, Alexander Mazo, Janice L. Walker

Department of Biochemistry and Molecular Biology Faculty Papers

Cell reprogramming to a myofibroblast responsible for the pathological accumulation of extracellular matrix is fundamental to the onset of fibrosis. Here, we explored how condensed chromatin structure marked by H3K72me3 becomes modified to allow for activation of repressed genes to drive emergence of myofibroblasts. In the early stages of myofibroblast precursor cell differentiation, we discovered that H3K27me3 demethylase enzymes UTX/KDM6B creates a delay in the accumulation of H3K27me3 on nascent DNA revealing a period of decondensed chromatin structure. This period of decondensed nascent chromatin structure allows for binding of pro-fibrotic transcription factor, Myocardin-related transcription factor A (MRTF-A) to nascent DNA. …

A Computationally Designed Ace2 Decoy Has Broad Efficacy Against Sars-Cov-2 Omicron Variants And Related Viruses In Vitro And In Vivo, Brandon Havranek, Graeme Walker Lindsey, Yusuke Higuchi, Yumi Itoh, Tatsuya Suzuki, Toru Okamoto, Atsushi Hoshino, Erik Procko, Shahidul M. Islam

SKMC Student Presentations and Publications

SARS-CoV-2, especially B.1.1.529/omicron and its sublineages, continues to mutate to evade monoclonal antibodies and antibodies elicited by vaccination. Affinity-enhanced soluble ACE2 (sACE2) is an alternative strategy that works by binding the SARS-CoV-2 S protein, acting as a 'decoy' to block the interaction between the S and human ACE2. Using a computational design strategy, we designed an affinity-enhanced ACE2 decoy, FLIF, that exhibited tight binding to SARS-CoV-2 delta and omicron variants. Our computationally calculated absolute binding free energies (ABFE) between sACE2:SARS-CoV-2 S proteins and their variants showed excellent agreement to binding experiments. FLIF displayed robust therapeutic utility against a broad range …

Cardiac Biomarkers Differentiate Kawasaki Disease From Multisystem Inflammatory Syndrome In Children Associated With Covid-19, Mollie Walton

Research Days

Background: Kawasaki disease (KD) and Multisystem Inflammatory Syndrome in Children (MIS-C) associated with COVID-19 show considerable clinical overlap. The goal of this study was to determine if cardiac biomarkers can differentiate KD from MIS-C.

Objectives/Goal: The goal of this study was to determine if cardiac biomarkers differentiate KD from MIS-C.

Methods/Design: The International Kawasaki Disease Registry enrolled (n=2903) contemporaneous KD and MIS-C patients1st, 2020, through June 30th, 2022. The study population was confined to KD patients meeting American Heart Association KD criteria with no prior COVID-19 infection and MIS-C patients meeting Centers for Disease Control and Prevention criteria with confirmed …

The Correlation Between Serum C-Reactive Protein Level And Risk Of Future Cardiovascular Disease: A Neurodivergent Population Dilemma, Brandon Cunha, Andrea Iannuzzelli, Venkateswar Venkataraman

Rowan-Virtua Research Day

Extensive research on neurotypical (NT) populations has demonstrated that a chronically elevated level of serum C Reactive Protein (CRP) is a strong predictor of future cardiovascular disease (CVD). Interestingly, many neurodivergent (ND) populations experience chronically elevated CRP levels higher than NT controls. Current research is concerned with establishing the significance of this relationship to accurately predict CVD risk for potentially at risk ND patients. To contribute to this gap in knowledge, the Rowan-Virtua Regional Integrated Special Needs (RISN) Center patient population will be studied to identify trends in baseline serum CRP levels across a multitude of ND conditions. A clinical …

Photodynamic Therapy Agents: The Power Of Mjöllnir To Eradicate Cancer, Sidney M. Hopper

Honors College Theses

After its discovery back in the 1900s, photosensitizers became a critical study for potential treatments and cures for medical issues, including cancer. It was discovered that porphyrins appeared to target and accumulate in proliferating cells, and to reach the cells, a certain wavelength of light with maximum absorbance associated with the porphyrin was necessary to achieve cell death. Photodynamic therapy involves making use of porphyrins or metalloporphyrins as activators when exposed to such light. When activated, these compounds generate reactive oxygen species (ROS), such as HO- or O2-, which can react with nucleic acids found in DNA and RNA. In …

Nicotinamide Riboside And Beta-Hydroxybutyrate Activate Parallel Pathways For C. Elegans Lifespan Extension, Mckenzie Peters

Undergraduate Honors Theses

Supplementation with nicotinamide riboside (NR), a form of vitamin B3 and a precursor of nicotinamide adenine dinucleotide (NAD⁺) extends lifespan in the nematode C. elegans and delays aging-related pathologies in mammals. During aging, levels of NAD⁺ decline causing metabolic dysfunction and oxidative damage. Studies in C. elegans found that when NR was administered during larval development it induced the mitochondrial unfolded protein response (UPR^mt), which is frequently associated with lifespan extension. Both calorie restriction (CR) and ketogenic diets (KD) have been shown to extend lifespan, in part through increasing NAD⁺ and through increasing levels …

An Investigation On The Effect Of Conserved Hinge Histidine On Influenza Hemagglutinin(Ha2) Protein Conformation Using Md Simulations, Nada Tolba

Chemistry & Biochemistry Undergraduate Honors Theses

Hemagglutinin is a protein on the surface of Human Influenza Viruses.¹ It is composed of two glycopolypeptide domains, the HA1 and HA2 domains. Previous studies have found that across different strains of Influenza viruses, HIS435 residues remain conserved.⁴ In studies where mutations occurred in hinge-site histadine residues, the Influenza virus was inactive.⁴ These investigations indicated a significant role of HIS435 (hinge-site histadines) in virulence. Four systems were created using Molecular dynamics (MD) simulations. Each system was composed of an Isolated HA2 trimer solvated in a 150 mM NaCl rectangular water box at 310 K under isobaric and …

Design And Synthesis Of Peripherally Selective Endocannabinoid Enzyme Inhibitors For Ocular Indications, Kezia Reji Thomas

Senior Honors Theses

Peripherally selective compounds have been found to stimulate endocannabinoid receptor activity, which has been observed to have positive physiological effects such as ocular wound healing and inflammation control. The activation of the cannabinoid 1 receptor via binding of the endogenous ligands, anandamide and 2-arachidonoylglycerol, has been indicated to elicit these effects. Both ligands are controlled by two hydrolase enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), which can be targeted for therapeutic inhibition. Sulfonamide derivatives of JZL195 containing carbamate functionalities in the southern region of the inhibitor compounds were produced using novel carbamate exchange reactions. Polar functionalities were …

The Wnt Pathway Protein Dvl1 Targets Somatostatin Receptor 2 For Lysosome-Dependent Degradation, Heather S Carr, Yan Zuo, Jeffrey A Frost

Student and Faculty Publications

The Somatostatin receptor 2 (Sstr2) is a heterotrimeric G protein-coupled receptor that is highly expressed in neuroendocrine tumors and is a common pharmacological target for intervention. Unfortunately, not all neuroendocrine tumors express Sstr2, and Sstr2 expression can be downregulated with prolonged agonist use. Sstr2 is rapidly internalized following agonist stimulation and, in the short term, is quantitatively recycled back to the plasma membrane. However, mechanisms controlling steady state expression of Sstr2 in the absence of agonist are less well described. Here, we show that Sstr2 interacts with the Wnt pathway protein Dvl1 in a ligand-independent manner to target Sstr2 for …

Candidate Variants In Dna Replication And Repair Genes In Early-Onset Renal Cell Carcinoma Patients Referred For Germline Testing, Elena V. Demidova, Ilya G. Serebriiskii, Ramilia Vlasenkova, Simon Kelow, Mark D. Andrake, Tiffiney R. Hartman, Tatiana Kent, James Virtucio, Gail L. Rosen, Richard T. Pomerantz, Roland L. Dunbrack, Erica A. Golemis, Michael J. Hall, David Y.T. Chen, Mary B. Daly, Sanjeevani Arora

Department of Biochemistry and Molecular Biology Faculty Papers

Background: Early-onset renal cell carcinoma (eoRCC) is typically associated with pathogenic germline variants (PGVs) in RCC familial syndrome genes. However, most eoRCC patients lack PGVs in familial RCC genes and their genetic risk remains undefined.

Methods: Here, we analyzed biospecimens from 22 eoRCC patients that were seen at our institution for genetic counseling and tested negative for PGVs in RCC familial syndrome genes.

Results: Analysis of whole-exome sequencing (WES) data found enrichment of candidate pathogenic germline variants in DNA repair and replication genes, including multiple DNA polymerases. Induction of DNA damage in peripheral blood monocytes (PBMCs) significantly elevated numbers of …

Computational Design And Molecular Modeling Of Morphine Derivatives For Preferential Binding In Inflamed Tissue, Makena Augenstein, Nayiri Alexander, Matthew Gartner

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

The opioid epidemic has impacted over 10 million Americans in 2019. Opioids, like morphine, bind non-selectively in both peripheral tissue, leading to effective pain relief, and central tissue, resulting in dangerous side effects and addiction. The inflamed conditions of injured tissues have a lower pH (pH = 6–6.5) environment than healthy tissue (pH = 7.4). We aim to design a morphine derivative that binds selectively within inflamed tissue using molecular extension and dissection techniques. Morphine binds to the μ-opioid receptor (MOR) when the biochemically active amine group is protonated. Fluorination of a β-carbon from the tertiary amine group led to …