Medical Biochemistry Commons^™

Hammerhead-Type Fxr Agonists Induce An Enhancer Rna Fincor That Ameliorates Nonalcoholic Steatohepatitis In Mice, Jinjing Chen, Ruoyu Wang, Feng Xiong, Hao Sun, Byron Kemper, Wenbo Li, Jongsook Kemper

Journal Articles

The nuclear receptor, farnesoid X receptor (FXR/NR1H4), is increasingly recognized as a promising drug target for metabolic diseases, including nonalcoholic steatohepatitis (NASH). Protein-coding genes regulated by FXR are well known, but whether FXR also acts through regulation of long non-coding RNAs (lncRNAs), which vastly outnumber protein-coding genes, remains unknown. Utilizing RNA-seq and global run-on sequencing (GRO-seq) analyses in mouse liver, we found that FXR activation affects the expression of many RNA transcripts from chromatin regions bearing enhancer features. Among these we discovered a previously unannotated liver-enriched enhancer-derived lncRNA (eRNA), termed FXR-induced non-coding RNA (

Unraveling Sorafenib Resistance In Hepatocellular Carcinoma: Exploring Key Facets, Dennis Kwabiah, Kyle Doxtater, Yamile Abuchard, Sophia Leslie, Ricardo Pequeno Bracho, Shaibir Hussain, Manish K. Tripathi

Research Symposium

Hepatocellular carcinoma (HCC) stands as the prevalent form of primary liver cancer worldwide, diagnosing over half a million new cases annually. Surgical interventions like hepatectomy and liver transplantation offer a potential cure for early-stage HCC. However, the prognosis for advanced stages remains grim due to drug resistance, particularly with high refractoriness rates. Sorafenib, a tyrosine kinase inhibitor, is an approved treatment for advanced HCC. Despite its use, the overall survival extension for these patients remains limited due to the drug's ineffectiveness, and the mechanism behind advanced HCC's resistance to sorafenib remains elusive. TCGA analysis of HCC patient cohorts reveals elevated …

Hif Expression In Clear-Cell Renal Cell Carcinoma (Ccrcc) Tumors Of Adults With And Without Obstructive Sleep Apnea (Osa), Olivia Heppell, Carlos Guerra Londono, Nilesh Gupta

Medical Student Research Symposium

Introduction: Upregulation of hypoxia-inducible factors (HIF) is an important pathological feature shared by clear cell renal cell carcinoma (ccRCC) and obstructive sleep apnea (OSA). However, it is unclear whether OSA alters the pathogenesis of ccRCC via HIF expression.

Methods: A retrospective cohort of adults undergoing nephrectomy for ccRCC was identified electronically (IRB#16040-1). The diagnosis of OSA was established with preoperative STOP-BANG scores or polysomnography. A consecutive sample of 20 individuals with and 20 without OSA was selected. Clinical characteristics and pathology results were reviewed. Resected tumor sections were immunohistochemically stained for HIF-1& HIF-2 at antibody dilutions of 1:150. Intensity and …

A Mutation In F-Actin Polymerization Factor Suppresses The Distal Arthrogryposis Type 5 Piezo2 Pathogenic Variant In Caenorhabditis Elegans, Xiaofei Bai, Harold E Smith, Luis O Romero, Briar Bell, Valeria Vásquez, Andy Golden

Journal Articles

The mechanosensitive PIEZO channel family has been linked to over 26 disorders and diseases. Although progress has been made in understanding these channels at the structural and functional levels, the underlying mechanisms of PIEZO-associated diseases remain elusive. In this study, we engineered four PIEZO-based disease models using CRISPR/Cas9 gene editing. We performed an unbiased chemical mutagen-based genetic suppressor screen to identify putative suppressors of a conserved gain-of-function variant pezo-1[R2405P] that in human PIEZO2 causes distal arthrogryposis type 5 (DA5; p. R2718P). Electrophysiological analyses indicate that pezo-1(R2405P) is a gain-of-function allele. Using genomic mapping and whole-genome sequencing approaches, we identified a …

Efficacy Of Supplemental Ultrasound-Guided Pericapsular Nerve Group (Peng) Block Combined With Lateral Femoral Cutaneous Nerve Block In Patients Receiving Local Infiltration Analgesia After Hip Fracture Surgery: A Prospective Randomized Controlled Trial., Seung-Hee Yoo, Min-Jin Lee, Min-Hyouk Beak, Won-Joong Kim

Journal Articles

No abstract provided.

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

Journal Articles

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 …

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. …

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

Journal Articles

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: …

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

Journal Articles

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 …

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

Journal Articles

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. …

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 …

Substrate Electronics Dominate The Rate Of Reductive Dehalogenation Promoted By The Flavin-Dependent Iodotyrosine Deiodinase, Anton Kozyryev, Daniel Lemen, Jessica Dunn, Steven E Rokita

Journal Articles

Iodotyrosine deiodinase (IYD) is unusual in its reliance on flavin to promote reductive dehalogenation of halotyrosines under aerobic conditions. Applications of this activity can be envisioned for bioremediation, but expansion of its specificity requires an understanding of the mechanistic steps that limit the rate of turnover. Key processes capable of controlling steady-state turnover have now been evaluated and described in this study. While proton transfer is necessary for converting the electron-rich substrate into an electrophilic intermediate suitable for reduction, kinetic solvent deuterium isotope effects suggest that this process does not contribute to the overall efficiency of catalysis under neutral conditions. …

Mechanosensitive Membrane Proteins: Usual And Unusual Suspects In Mediating Mechanotransduction, Miriam B Goodman, Elizabeth S Haswell, Valeria Vásquez

Journal Articles

This Viewpoint, which accompanies a Special Issue focusing on membrane mechanosensors, discusses unifying and unique features of both established and emerging mechanosensitive (MS) membrane proteins, their distribution across protein families and phyla, and current and future challenges in the study of these important proteins and their partners. MS membrane proteins are essential for tissue development, cellular motion, osmotic homeostasis, and sensing external and self-generated mechanical cues like those responsible for touch and proprioception. Though researchers' attention and this Viewpoint focus on a few famous ion channels that are considered the usual suspects as MS mechanosensors, we also discuss some of …

Harnessing Transcriptionally Driven Chromosomal Instability Adaptation To Target Therapy-Refractory Lethal Prostate Cancer., Brittiny Dhital, Sandra Santasusagna, Perumalraja Kirthika, Michael Xu, Peiyao Li, Marc Carceles-Cordon, Rajesh K. Soni, Zhuoning Li, Ronald C. Hendrickson, Matthew J. Schiewer, William K. Kelly, Cora N. Sternberg, Jun Luo, Amaia Lujambio, Carlos Cordon-Cardo, Monica Alvarez-Fernandez, Marcos Malumbres, Haojie Huang, Adam Ertel, Josep Domingo-Domenech, Veronica Rodriguez-Bravo

Kimmel Cancer Center Papers, Presentations, and Grand Rounds

Metastatic prostate cancer (PCa) inevitably acquires resistance to standard therapy preceding lethality. Here, we unveil a chromosomal instability (CIN) tolerance mechanism as a therapeutic vulnerability of therapy-refractory lethal PCa. Through genomic and transcriptomic analysis of patient datasets, we find that castration and chemotherapy-resistant tumors display the highest CIN and mitotic kinase levels. Functional genomics screening coupled with quantitative phosphoproteomics identify MASTL kinase as a survival vulnerability specific of chemotherapy-resistant PCa cells. Mechanistically, MASTL upregulation is driven by transcriptional rewiring mechanisms involving the non-canonical transcription factors androgen receptor splice variant 7 and E2F7 in a circuitry that restrains deleterious CIN and …

Protein S In Coagulation And Inflammation, Martha Mega Silvia Sim

Theses and Dissertations--Molecular and Cellular Biochemistry

Protein S (PS) is a key regulator, which links inflammation and coagulation and performs multiple proposed functions in both processes. PS exists in the blood as a free soluble form (~40%), bound to complement component 4b-binding protein/ C4BP (~60%), and packaged in platelet α-granules (~2.5%). Subendothelial tissue factor (TF), upon exposure to blood, initiates coagulation, a proteolytic cascade which results in the activation of thrombin, the enzyme responsible for formation of a fibrin clot. PS is a critical anticoagulant that inhibits multiple steps of this process. Only the free fraction of PS has full anticoagulant properties, as C4BP blocks this …

Provider Education On Annual B12 Levels In Patients On Metformin, Callan Gravel-Pucillo Mms

Family Medicine Clerkship Student Projects

Education of primary care providers about the current recommendations, guidelines, and caveats surrounding obtaining annual B12 levels in patients on metformin to screen for deficiency. Education was based off of informal survey results assessing providers' current practices and the preferred medium through which they wanted to recieve educational content. Educational content was presented in a flowchart format for ease of use and distributed at both practice sites for providers to hang at their workstations.

Effects Of Atrazine Exposure On Human Bone Marrow-Derived Mesenchymal Stromal Cells Assessed By Combinatorial Assay Matrix, Crystal C Uwazie, Bonnie M Pirlot, Tyler U Faircloth, Mihir Patel, Rhett N Parr, Halie M Zastre, Peiman Hematti, Guido Moll, Devi Rajan, Raghavan Chinnadurai

Journal Articles

INTRODUCTION: Mesenchymal Stromal/Stem cells (MSCs) are an essential component of the regenerative and immunoregulatory stem cell compartment of the human body and thus of major importance in human physiology. The MSCs elicit their beneficial properties through a multitude of complementary mechanisms, which makes it challenging to assess their phenotype and function in environmental toxicity screening. We here employed the novel combinatorial assays matrix approach/technology to profile the MSC response to the herbicide Atrazine, which is a common environmental xenobiotic, that is in widespread agricultural use in the US and other countries, but banned in the EU. Our here presented approach …

Association Of Smoking With Total Oxidant And Antioxidant Levels In Breast Milk, Nesibe Yildiz, Adnan Yilmaz

Makara Journal of Health Research

Background: Breast milk is a natural food that contains all the fluids, energy, and nutrients necessary for the optimum growth and development of newborns. Smoking is a public health problem that has harmful effects on the mother and baby. This study aimed to examine the association of exposure to smoking with total oxidant status (TOS) and total antioxidant status (TAS) in breast milk.

Methods: Healthy mothers without any health problems during their pregnancy and lactation periods were selected as subjects. Eighty-eight milk samples (44 in the smoking group and 44 in the nonsmoking group) were examined. TOS and …

Unilateral ‘Crazy-Paving’ Pattern: An Exceptional Presentation Of Squamous Cell Carcinoma Of The Lung, Sumeera Banday, Shamim U Khan, Sabina Khan, Surinderpal S Anand, Ashok Shah

Journal Articles

The 'crazy-paving' pattern on high resolution computed tomography (HRCT) is a distinct imaging appearance that is still considered to be a radiological hallmark of pulmonary alveolar proteinosis. However, since its first description about three decades ago, more than 40 different clinical entities presenting as 'crazy-paving' patterns have been documented. This rather remarkable but uncommon imaging appearance is now considered to be a non-specific manifestation. A 62-year-old male referred for evaluation of productive cough, breathlessness and fever presented with 'crazy-paving' pattern on HRCT. Endobronchial biopsy done on presentation was consistent with the diagnosis of squamous cell carcinoma. This report highlights this …

Right Ventricular Energetic Biomarkers From 4d Flow Cmr Are Associated With Exertional Capacity In Pulmonary Arterial Hypertension., Xiaodan Zhao, Shuang Leng, Ru-San Tan, Ping Chai, Tee Joo Yeo, Jennifer Ann Bryant, Lynette L S Teo, Marielle V Fortier, Wen Ruan, Ting Ting Low, Ching Ching Ong, Shuo Zhang, Rob J Van Der Geest, John C Allen, Marina Hughes, Pankaj Garg, Teng Hong Tan, James W Yip, Ju Le Tan, Liang Zhong

Journal Articles

BACKGROUND: Cardiovascular magnetic resonance (CMR) offers comprehensive right ventricular (RV) evaluation in pulmonary arterial hypertension (PAH). Emerging four-dimensional (4D) flow CMR allows visualization and quantification of intracardiac flow components and calculation of phasic blood kinetic energy (KE) parameters but it is unknown whether these parameters are associated with cardiopulmonary exercise test (CPET)-assessed exercise capacity, which is a surrogate measure of survival in PAH. We compared 4D flow CMR parameters in PAH with healthy controls, and investigated the association of these parameters with RV remodelling, RV functional and CPET outcomes.

METHODS: PAH patients and healthy controls from two centers were prospectively …

Clinicopathological And Prognostic Significance Of Cxcr4 Expression In Osteosarcoma: A Meta-Analysis, I Gusti Ngurah Ananda Wira Kusuma, Grace Yulia Alphani Yapson, John Nolan, I Gede Eka Wiratnaya, I Gede Putu Supadmanaba

BioMedicine

Background: The C-X-C Motif Chemokine Receptor (CXCR4) is an oncogene that has been widely studied and associated with worse clinicopathological features and prognosis outcomes in many types of cancer. Besides that, significance of CXCR4 expression on clinicopathological features and prognostic factors in osteosarcoma (OS) requires further validation.

Aim: We conducted a meta-analysis to evaluate the association between positive CXCR4 expression with clinicopathological features and prognosis in OS.

Methods: Literature searches on Pubmed, Cochrane Library, and Web of Science were conducted systematically up to December 2021 to find relevant references. The effects of CXCR4 expression on clinicopathological characteristics and prognostic were …

Glucose Uptake By Glut1 In Photoreceptors Is Essential For Outer Segment Renewal And Rod Photoreceptor Survival, Lauren L. Daniele, John Y.S. Han, Ivy S Samuels, Ravikiran Komirisetty, Nikhil Mehta, Jessica L Mccord, Minzhong Yu, Yekai Wang, Kathleen Boesze-Battaglia, Brent A Bell, Jianhai Du, Neal S Peachey, Nancy J. Philp

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Photoreceptors consume glucose supplied by the choriocapillaris to support phototransduction and outer segment (OS) renewal. Reduced glucose supply underlies photoreceptor cell death in inherited retinal degeneration and age-related retinal disease. We have previously shown that restricting glucose transport into the outer retina by conditional deletion of Slc2a1 encoding GLUT1 resulted in photoreceptor loss and impaired OS renewal. However, retinal neurons, glia, and the retinal pigment epithelium play specialized, synergistic roles in metabolite supply and exchange, and the cell-specific map of glucose uptake and utilization in the retina is incomplete. In these studies, we conditionally deleted Slc2a1 in a pan-retinal or …

Kalium Channelrhodopsins Are Natural Light-Gated Potassium Channels That Mediate Optogenetic Inhibition, Elena G Govorunova, Yueyang Gou, Oleg A Sineshchekov, Hai Li, Xiaoyu Lu, Yumei Wang, Leonid S Brown, François St-Pierre, Mingshan Xue, John L Spudich

Journal Articles

Channelrhodopsins are used widely for optical control of neurons, in which they generate photoinduced proton, sodium or chloride influx. Potassium (K+) is central to neuron electrophysiology, yet no natural K+-selective light-gated channel has been identified. Here, we report kalium channelrhodopsins (KCRs) from Hyphochytrium catenoides. Previously known gated potassium channels are mainly ligand- or voltage-gated and share a conserved K+-selectivity filter. KCRs differ in that they are light-gated and have independently evolved an alternative K+ selectivity mechanism. The KCRs are potent, highly selective of K+ over Na+, and open in less than 1 ms following photoactivation. The permeability ratio PK/PNa of …

Mechanism Of Rare Variant In Acta2, P.Arg149cys, Driving Diverse Vascular Disease, Kaveeta Kaw

Dissertations & Theses (Open Access)

Heterozygous variants in ACTA2 (smooth muscle (SM) α-actin) predispose to thoracic aortic aneurysms and dissections (TAAD) and early-onset coronary artery disease (CAD). The most common ACTA2 mutation is a genetic alteration of arginine 149 to a cysteine, ACTA2 p.Arg149Cys, which accounts for disease in 24% of all ACTA2 mutation carriers.(1) ACTA2 p.Arg149Cys mutation carriers present with either TAAD or CAD but rarely have both diseases. To identify the molecular mechanisms dictating whether an individual with ACTA2 p.Arg149Cys develops TAAD or CAD, CRISPR/Cas9 technology was used to generate the mutant mouse, Acta2^R149C/+, in a C57BL6 background. Acta2^R149C/+ mice …

Applying Mci-062, A Novel Pan-Ras Inhibitor, To Treat Kras-Mutant Lung Cancer, Richard Fu

Honors Theses

RAS is a prevalent oncogene that is mutated in 27% of human cancers. Gain-of-function RAS mutations activate multiple downstream pathways, including the RAS-RAF-MEK-ERK and PI3K/AKT/mTOR pathways, which are critical in tumorigenesis and cancer cell proliferation. RAS proteins such as KRAS, a member of the RAS protein family, and their downstream effectors are attractive targets for cancer therapy since their mutations act as frequent drivers in lung, colorectal, and pancreatic cancers. However, RAS proteins have relatively smooth surfaces that lack traditional binding pockets, making inhibitors specific to RAS difficult to create. Recently, a novel small molecule pan-RAS inhibitor named MCI-062 was …

Applying Mci-062, A Novel Pan-Ras Inhibitor, To Treat Kras-Mutant Lung Cancer., Richard Fu

Poster Presentations

Honors thesis poster presentation.

RAS, one of the most prevalent oncogenes, is mutated in 27% of human cancers. Gainof- function RAS mutations activate multiple downstream pathways, including the RASRAF- MEK-ERK and PI3K/AKT/mTOR pathways, which are critical in tumorigenesis and cancer cell proliferation. The RAS proteins KRAS, HRAS, and NRAS along with their downstream effectors are attractive targets for cancer therapy since they act as frequent drivers in lung, colorectal, and pancreatic cancers. However, RAS proteins have relatively smooth surfaces that lack traditional binding pockets, making inhibitors specific to RAS difficult to create. Recently, a novel small molecule pan-RAS inhibitor named …