Cell and Developmental Biology Commons^™

Ferroptotic Cardiomyocytes Regulate Angiogenesis In The Regenerative Mouse Heart After Myocardial Infarction Through Direct And Indirect Mechanisms, Rebecca Ashley Stairley

MUSC Theses and Dissertations

Cardiovascular diseases (CVDs) are the leading cause of death in the United States, and heart attack occurs every 40 seconds in the US. A myocardial infarction (MI), or heart attack, results in ischemic injury and cardiomyocyte (CM) death. Mature mammalian CM renewal in the heart is insufficient to repopulate the lost tissue. However, the neonatal mouse heart retains its regenerative capacity through the first week of life, providing a valuable model to identifying regenerative factors.

Recent work by our lab revealed that the main mechanism of CM death in the heart post-MI is ferroptosis. In this study, we investigate the …

Identification Of New Leads Against Ubiquitin Specific Protease-7 (Usp7): A Step Towards The Potential Treatment Of Cancers, Sumaira Javaid, Seema Zadi, Muhammad Awais, Atai-Tul Wahab, Humaira Zafar, Innokentiy Maslennikov, M. Iqbal Choudhary

Pharmacy Faculty Articles and Research

Ubiquitin-specific protease-7 (USP7) is an important drug target as it regulates multiple proteins and genes (such as MDM2 and p53) with roles in cancer progression. Its inhibition can hinder the function of oncogenes, increase tumor suppression, and enhance immune response. The current study was designed to express USP7 in a prokaryotic system, followed by screening of small molecules against it using biophysical methods, primarily STD-NMR technique. Among them, 12 compounds showed interaction with USP7 as inferred from NMR-based screening. These compounds further caused destabilization of USP7 by reducing its melting temperature (T_m) up to 6 °C in …

Electric Potential Energy Optimized 3d Radial Sampling Trajectories For Mri, Christopher Huynh, Datta Singh Goolaub, Christopher K Macgowan

Faculty, Staff and Students Publications

A novel method for creating “golden” 3D center-out radial MRI sampling trajectories was developed and analyzed. This method, called ELECTRO (ELECTRic potential energy Optimized), uses repulsive forces to minimize electric potential energy. An objective function , the electric potential energies of all subsets of consecutive readouts in a 3D radial trajectory, and its reduced form were minimized using a multi-stage optimization strategy. A metric called normalized mean nearest neighbor angular distance (NMNA) was proposed for describing distributions of points on a sphere. ELECTRO and other relevant golden trajectories were compared in silico using NMNA and point spread function analysis. Consecutive …

Effects Of Cadherin Mediated Contact Normalization On Oncogenic Src Kinase Mediated Gene Expression And Protein Phosphorylation, Rachel E Nicoletto, Cayla J Holdcraft, Ariel C Yin, Edward P Retzbach, Stephanie A Sheehan, Amanda A Greenspan, Christopher M Laugier, Jason Trama, Caifeng Zhao, Haiyan Zheng, Gary S Goldberg

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Nontransformed cells form heterotypic cadherin junctions with adjacent transformed cells to inhibit tumor cell growth and motility. Transformed cells must override this form of growth control, called "contact normalization", to invade and metastasize during cancer progression. Heterocellular cadherin junctions between transformed and nontransformed cells are needed for this process. However, specific mechanisms downstream of cadherin signaling have not been clearly elucidated. Here, we utilized a β-catenin reporter construct to determine if contact normalization affects Wnt signaling in transformed cells. β-catenin driven GFP expression in Src transformed mouse embryonic cells was decreased when cultured with cadherin competent nontransformed cells compared to …

Hepatic Targets To Control Blood Glucose And Potentially Aid In The Treatment Of Diabetes, Rena A. Velissarios

PANDION: The Osprey Journal of Research and Ideas

Maintaining glucose homeostasis is extremely important to remain in good health and prevent disease. This homeostasis is achieved via the regulation of hepatic metabolic pathways like gluconeogenesis and glycogenesis by insulin, which is expressed during high blood glucose. Insulin is responsible for facilitating the uptake of glucose into other tissues from the blood, as well as signaling whether to stimulate or slow glucose metabolism in the liver. Hyperglycemia is one of the main effects of diabetes, a disease characterized by the body’s inability to produce or respond to insulin. Without insulin, hepatic glucose output continues and blood glucose accumulates, causing …

Denaturation Station: The Effect Of Guanidinium Chloride On Yeast Flocculation, Taylor Pulley, Jade Riddle, Angelina Scotece

Fall Showcase for Research and Creative Inquiry

Flocculation is a phenomenon found in yeast such as Saccharomyces cerevisiae in which cells aggregate in response to stressful environmental conditions. This occurs as the result of the interaction of flocculin proteins on the plasma membrane with mannose residues on the surface of other yeast cells which is often exploited in the brewing process to avoid expensive filtration steps. Guanidine is a chaotropic agent which reduces the stability of proteins by weakening the hydrophobic effect. Since it is believed that flocculation is dependent on protein-mannose binding interactions, if the structure of the flocculin proteins is altered by guanidine, their functionality …

Understanding The Influence Of Bone Marrow Endothelial Cells On Primary Human Megakaryocytic-Erythroid Progenitor Cell Fate, Vedaamrutha Reddy

Holster Scholar Projects

The human bone marrow is a complex microenvironment comprised of hematopoietic, stromal, and bone marrow endothelial cells (BMECs). This study builds on previous findings to explore the regulatory role of BMECs in influencing the expansion and lineage choice of megakaryocytic-erythroid progenitors (MEPs). Understanding these interactions has the potential to advance transfusion medicine and improve treatments for conditions like thrombocytopenia and anemia. Due to complications with isolating human BMEC, we transitioned to a murine model. Murine BMECs were isolated and magnetic cell separation was employed to enrich for endothelial cells (ECs), which were then cultured over a 20-day period using standard …

Characterization Of Developmentally Downregulated Nfe2l3 In Retinal Ganglion Cell Survival And Axon Regeneration, Lucy Homer

Holster Scholar Projects

Retinal ganglion cells (RGCs) are central nervous system projection neurons essential for transmitting visual information from the eye to the brain. Damage to RGCs, caused by conditions such as glaucoma and traumatic optic neuropathy (TON), may lead to vision loss or blindness, as adult RGCs lack regenerative capacity. This study focuses on Nfe2l3 (Nrf3), a developmentally downregulated transcription factor known to mediate cellular responses to oxidative stress, a key pathological event following optic nerve injury. We hypothesized that overexpressing Nfe2l3 in RGCs would enhance their survival and promote axon regeneration after optic nerve crush (ONC) injury. To test this, we …

Conditional Deletion Of Ceacam1 In Hepatic Stellate Cells Causes Their Activation, Harrison T. Muturi, Hilda E. Ghadieh, Suman Asalla, Sumona G. Lester, Getachew D. Belew, Sobia Zaidi, Raziyeh Abdolahipour, Abhishek P. Shrestha, Agnes O. Portuphy, Hannah L. Stankus, Raghd Abu Helal, Stefaan Verhulst, Sergio Duarte, Ali Zarrinpar, Leo A. Van Grunsven, Scott L. Friedman, Robert F. Schwabe, Terry D. Hinds, Jr., Sivarajan Kumarasamy, Sonia M. Najjar

Markey Cancer Center Faculty Publications

Objectives: Hepatic CEACAM1 expression declines with advanced hepatic fibrosis stage in patients with metabolic dysfunction-associated steatohepatitis (MASH). Global and hepatocyte-specific deletions of Ceacam1 impair insulin clearance to cause hepatic insulin resistance and steatosis. They also cause hepatic inflammation and fibrosis, a condition characterized by excessive collagen production from activated hepatic stellate cells (HSCs). Given the positive effect of PPARg on CEACAM1 transcription and on HSCs quiescence, the current studies investigated whether CEACAM1 loss from HSCs causes their activation.

Methods: We examined whether lentiviral shRNA-mediated CEACAM1 donwregulation (KD-LX2) activates cultured human LX2 stellate cells. We also generated LratCre þ Cc1fl/fl mutants …

Development And Quantification Of An Attachment Assay For Epidermal Cells To Varying Extracellular Matrix Dilutions, Julian Vargas '26, Colleen L. Doçi

Annual Student Research Poster Session

The concept of cellular attachment is cells interacting with the extracellular matrices surrounding it. Extracellular matrices are made of various components, and it has been shown that the interactions differ between different classes of extracellular matrices. The basement membrane plays a critical role in the structure and function of the epidermis, the outermost layer of the skin. It is composed of key extracellular matrix components, which are crucial for structural stability of the skin and for maintaining the integrity of the epidermis. Through components like collagen, laminin, and proteoglycans, the BM facilitates communication between the epidermal cells and the connective …

The Effects Of Cannabinoids On Migration-Related Protein Expression In Ewing’S Sarcoma, Allison Lashall

Theses

Ewing’s sarcoma is an aggressive pediatric bone cancer that has low five-year survival rates, primarily due to metastatic disease and resistance of recurring tumors to traditional treatment options; therefore, novel treatment options are needed. The compound cannabidiol (CBD) has been shown to reduce cell viability, migration, and invasion in several tumor types, though the cellular mechanism of action is not well understood. Our lab has demonstrated the ability of CBD to reduce viability, migration, and invasion of Ewing’s sarcoma cells in vitro and is investigating differential protein and cytokine expression of known mediators of migration, such as intercellular adhesion molecule …

Challenges And Coping Strategies Among Caregivers Of Children With Cancer Receiving Care At A National Referral Hospital In Kenya, Doris Machaki, Albanus Kyalo Mutisya, Jostine Mutinda, Sherry Oluchina, Samwel Maina Gatimu

School of Nursing & Midwifery, East Africa

Background: The number of children diagnosed with cancer is expected to increase by 2050. The caring aspect of these children is usually left to members of the family, more so the mothers. Caregivers are usually faced with various challenges, such as financial issues, social stigma, and emotional and psychological issues. Caregivers use various coping strategies to manage the challenges they experience in the caring process, which can be positive or negative coping strategies.

Objective: To explore the challenges and coping strategies of caregivers of children with cancer receiving care at a national referral hospital in Kenya.

Methods: This study employed …

Identification Of Inflammatory Factors Contributing To Foaming In Atherosclerosis, Kavya Podila

Holster Scholar Projects

According to the National Institute of Health (NIH), atherosclerosis is attributed to the majority of cardiovascular disease (CVD) cases and is the leading cause of mortality in the US and worldwide. Despite significant medical advancements, the risk of cardiovascular events remains, warranting further mechanistic and pathogenic investigation. Advances in high-resolution omics profiling and the development of novel data-analytic bioinformatic tools previously enabled the novel discovery of two distinct programs in foaming, the central process in atherogenesis. The programs are pathogenic and homeostatic foaming, with the pathogenic foaming program being positively associated with disease. Using single-cell RNA sequencing (scRNA-seq) data from …

Metabolic Crossroads: Gaba Synthesis In Trichomonas Vaginalis Infection, Yesha Dhruv

Biochemistry and Molecular Biology

This study examines the gamma-aminobutyric acid (GABA) synthesis pathway in Trichomonas vaginalis infection of human HCT-8 cells, focusing on key enzymatic processes in glutamate conversion to GABA and metabolic adaptations. The hypothesis tested was that T. vaginalis modulates GABA metabolism to enhance host cell invasion and adaptation. Infection time-point studies, RNA sequencing, and aldehyde dehydrogenase (ALDH) assays were conducted. Comparisons between T. vaginalis strains Casu 2 and Casu 2/MOZ 2 revealed distinct infection dynamics. Casu 2 rapidly attached and replicated within an hour, peaking at 24 hours, while Casu 2/MOZ 2 exhibited delayed replication, peaking at 48 to 72 hours, …

Granulocyte Colony Stimulating Factor Promotes Scarless Tissue Regeneration, Jianhe Huang, Satish: Murphy Sati, Casey A. Spencer, Emmanuel Rapp, Stephen M. Prouty, Scott Korte, Olivia Ahart, Emily Sheng, Anna E. Kersh, Denis Leung, Thomas H. Leung, Leung, Denis H. Y.

Research Collection School Of Economics

Mammals typically heal with fibrotic scars, and treatments to regenerate human skin and hair without a scar remain elusive. We discovered that mice lacking C-X-C motif chemokine receptor 2 (CXCR2 knockout [KO]) displayed robust and complete tissue regeneration across three different injury models: skin, hair follicle, and cartilage. Remarkably, wild-type mice receiving plasma from CXCR2 KO mice through parabiosis or injections healed wounds scarlessly. A comparison of circulating proteins using multiplex ELISA revealed a 24-fold higher plasma level of granulocyte colony stimulating factor (G-CSF) in CXCR2 KO blood. Local injections of G-CSF into wild-type (WT) mouse wound beds reduced scar …

Effect Of Heat Stress On The Expression Of Circulating Cyto(Chemo)Kine And Inflammatory Markers In Broiler Chickens Selected For High- Or Low-Water Efficiency, Elizabeth S. Greene, Travis Tabler, Walter G. Bottje, Sara Orlowski, Sami Dridi

Poultry Science Faculty Publications and Presentations

Background:

Water scarcity is a current, significant global concern that will only increase under the pressure of climate change. Improving water efficiency of poultry is a new and promising area to help temper agriculture's future impact on fresh water availability. Here, we explored the effects of acute heat stress (HS) on circulating stress and inflammatory markers in 2 lines of broilers divergently selected for water efficiency. Methods:

Male chicks from low (LWE) and high water efficient (HWE) lines were raised in 12 environmental chambers (2 pens/chamber, 6 chambers/line, 20 birds/pen) under normal conditions until day 28. On day 29, birds …

Intercellular Mitochondrial Transfer Contributes To Microenvironmental Fate Redirection Of Mammary Cancer Cells, Julie Sofie Bjerring

Biomedical Sciences Theses & Dissertations

The dynamic cellular microenvironment, made up of resident cells and various macromolecules, differs markedly across tissues in the body. The multidirectional signals that cells receive from this microenvironment, along with the signaling they send back, heavily influence their physiology and behavior. Recent important findings have further validated this notion as the mammary microenvironment has been shown to suppress tumor progression by redirecting cancer cells to adopt a normal mammary epithelial progenitor fate in vivo. However, the mechanism(s) driving changes in metabolic reprogramming and cancer fate redirection is understudied. The work presented in this dissertation focuses on exploring the impact of …

Characterization Of Stealth Liposome-Based Nanoparticles Encapsulating Acat1/Soat1 Inhibitor F26: Potential Therapeutics For Niemann-Pick Type C And Other Neurodegenerative Diseases., Junghoon Lee

Dartmouth College Ph.D Dissertations

Cholesterol dysregulation is implicated in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) and Niemann-Pick type C disease (NPCD). This study focused on evaluating the potent ACAT1 inhibitor, F26, as a therapeutic strategy for NPCD. F26 demonstrated superior ACAT1 inhibition and efficacy compared to the previously studied inhibitor, F12511, both in vitro and in vivo. Notably, F26 exhibited enhanced pharmacokinetic properties, including prolonged duration of action and better brain retention, making it a more promising candidate for treating neurodegenerative diseases.

F26 was encapsulated in a liposome-based nanoparticle system, DSPE-PEG2000 with phosphatidylcholine (PC), for enhancing its …

Molecular Targets For Breast Cancer Therapy, Hamidreza Montazeri Aliabadi

Pharmacy Faculty Articles and Research

"Breast cancer is by far the most common cancer in women, and for a while, it surpassed lung cancer as the most diagnosed cancer, regardless of gender, in 2020 [1]. Chemotherapy and hormone therapy are still the first line of treatment, despite extensive research in molecularly targeted drugs. Therefore, triple negative breast cancer (TNBC) is still known as the most challenging type for treatment due to the limited identified targets. Inherent and acquired resistance are still major hurdles in breast cancer therapy, which further highlights the importance of identifying new molecular targets in this battle. The inherent resistance of unresponsive …

Characterizing Biomolecular Structure Features Through An Innovative Elliptical Dichroism Spectrometry For Cancer Detection, Yusuf Asad, Keerthi Priya Jangili, Amara Arshad, Maliha Elma, Komila Rasuleva, Alfred Akinlalu, Tommy Gao, Umamaheswara Rao Tida, Wenjie Xia, Dali Sun

Electrical and Computer Engineering: Faculty Scholarship

This research introduces a novel method for evaluating the structural features of biomolecules, utilizing our innovative Elliptical Dichroism (ED) spectrometer specifically designed for stereochemical analysis. By integrating ED spectrometry with autocorrelation (AC) analysis, we investigate the conformational characteristics of biological molecules such as amino acids, proteins, and extracellular vesicles (EVs) induced by elliptically polarized UV absorption. Our streamlined approach offers a cost-effective and portable solution with minimal sample consumption and supports multiple working modes to efficiently characterize biomolecular structures. The insight from this new approach demonstrates potential applications in using biomolecular characterization for cancer detection.

Effect Of Cytoplasmic Polyadenylation Element Protein Overexpression On The Development Of Bovine Cloned Embryos, Ying Liu

Funded Research Records

No abstract provided.

Enhanced Bmp Signaling Via Alk2 In Osteoclasts Decreases Bone Density In Mice, Yolanda V. Gutierrez, Hiroyuki Yamaguchi, Yuji Mishina, Yoshihiro Komatsu

Research Colloquium

Bone remodeling is a complex biological process that has been extensively studied. Bone Morphogenetic Proteins (BMPs) are recognized as one of the critical growth factors that coordinate bone remodeling. Previous studies have demonstrated that BMP signaling in osteoclasts has a positive effect on osteoclast function. However, little is known about how each BMP type I receptors control osteoclastogenesis. To investigate this question, we utilized the Cre-LoxP system to specifically activate BMP signaling through ALK2 in mice. We utilized Cathepsin K (Ctsk)-Cre driver to activate BMP signaling in osteoclasts in mice. Compared with aged- and gender-matched controls, gain-of-function of BMP mutant …

Honey: A Natural Recipe For The Management Of Pancreatic Cancer, Aun A. Bangash, Muhammad A. Bangash, Georgina Villanueva, Haider Ahsan, Shiza Khan, Rida Shareef, Mudassier Ahmad, Dae J. Kim, Sahir S. Alvi, Bilal B. Hafeez

Research Colloquium

Background: Pancreatic cancer (PanCa) is the fourth deadliest cancer worldwide and expected to become the second deadliest cancer by 2030. In the USA, the National Cancer Institute put forth a grim prediction stating that there will be 64,050 new cases in 2023 alone and about 50,000 of these patients will die. The first line treatment for pancreatic cancer is Folfrinox, a three-drug regimen consisting of 5-Fluorouracil, irinotecan, and oxaliplatin. The second line treatment is gemcitabine combined with paclitaxel. Only 19% of patients who are prescribed the former regimen survive past 18 months of treatment while just 6% of patients survive …

Keratin 17 Is A Prognostic And Predictive Biomarker In Pancreatic Ductal Adenocarcinoma, Lyanne Delgado-Coka, Lucia Roa-Peña, Sruthi Babu, Michael Horowitz, Emanuel Petricoin, Lynn Matrisian, Edik Blais, Natalia Marchenko, Felicia Allard, Ali Akalin, Wei Jiang, Md, Phd, Brent Larson, Andrew Hendifar, Vincent Picozzi, Minsig Choi, Kenneth Shroyer, Luisa Escobar-Hoyos

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

OBJECTIVES: To determine the role of keratin 17 (K17) as a predictive biomarker for response to chemotherapy by defining thresholds of K17 expression based on immunohistochemical tests that could be used to optimize therapeutic intervention for patients with pancreatic ductal adenocarcinoma (PDAC).

METHODS: We profiled K17 expression, a hallmark of the basal molecular subtype of PDAC, by immunohistochemistry in 2 cohorts of formalin-fixed, paraffin-embedded PDACs (n = 305). We determined a K17 threshold of expression to optimize prognostic stratification according to the lowest Akaike information criterion and explored the potential relationship between K17 and chemoresistance by multivariate predictive analyses.

RESULTS: …

Examination Of Oncogenic Effects Of Environmental Pollutants, Andrew Ackerman, Matthew Behling, Brock Earley, Janay Vacharasin

Journal of the South Carolina Academy of Science

Chemical byproducts produced by surrounding industrial complexes have polluted the local estuaries of Georgetown, South Carolina for several decades¹. Previous studies completed by the EPA and SCDNR showed that the estuaries contained carcinogenic pollutants released from the local manufacturing plants¹. One of the mentioned pollutants was dioxins which are produced during the paper bleaching process². Dioxins are highly toxic compounds that have various carcinogenic effects on the organisms that inhabit the area. These previous studies were conducted over thirty years ago. Therefore, a current study to determine if chemical byproducts are contaminating local estuaries …

Autophagy And Meiotic Fidelity In C. Elegans, Kaitlin E. Kosinski

Dissertations, Theses, and Capstone Projects

Autophagy is an evolutionarily conserved multi-step recycling process in which cellular material is enclosed in the double membrane-bound autophagosome, which fuses with the lysosome to degrade its contents. Autophagy is essential for development and cellular adaptation to environmental or intracellular stress and is an important regulator of germline stem cell homeostasis in the model nematode C. elegans. We sought to determine if autophagy is important for genome stability during meiosis and found that the core adult C. elegans autophagy genes bec-1, atg-7, unc-51, and atg-18 were all required for proper meiotic development of oocytes. Loss of these …

Effects Of Oxycodone On Placental Lineages: Evidence From The Transcriptome Profile Of Mouse Trophoblast Giant Cells, Zhen Lyua, Jessica A. Kinkadeb, Nathan J. Bivens, R. Michael Roberts, Trupti Joshi, Cheryl S. Rosenfeld

Biomedical Sciences

Pregnant women are often prescribed or abuse opioid drugs. The placenta is likely the key to understanding how opioids cause adverse pregnancy outcomes. Maternal oxycodone (OXY) exposure of pregnant mice leads to disturbances in the layer of invasive parietal trophoblast giant cells (pTGC) that forms the interface between the placenta and uterus. These cells are analogous to extravillous trophoblasts of the human placenta. They are crucial to coordinating the metabolic needs of the conceptus with those of the mother and are primary participants in the placenta–brain axis. Their large nuclear size, however, has precluded both single- cell (sc) and single- …

Novel Psychoplastogen Dm506 Reduces Cue-Induced Heroin-Seeking And Inhibits Tonic Gaba Currents In The Prelimbic Cortex, Kassandra Looschen, Shailesh N. Khatri, Malabika Maulik, Colin Salisbury, Alaina F. Carman, Katilyn Corriveau, Colton Smith, Dina Manetti, Maria Novella Romanelli, Hugo R. Arias, Cassandra D. Gipson, Swarup Mitra

Markey Cancer Center Faculty Publications

Opioid use disorder is a major public health crisis that is manifested by persistent drug-seeking behavior and high relapse frequency. Most of the available treatments rely on targeting opioid receptors using small molecules that do not provide sustained symptom alleviation. Psychoplastogens are a novel class of non-opioid drugs that produce rapid and sustained effects on neuronal plasticity, intended to produce therapeutic benefits. Ibogalogs are synthetic derivatives of iboga alkaloids that lack hallucinogenic or adverse side effects. In the current study, we examine the therapeutic potential of DM506, a novel ibogalog lacking any cardiotoxic or hallucinogenic effects, in cue-induced seeking behavior …

Complete Genome Sequence Of An Indian Outbreak Strain Of Chikungunya Virus, Eshna Laha, Deepak Jena, Viplov K. Biswas, Sharad Singh, Sunil K. Raghav, Asit K. Pattnaik, Soma Chattopadhyay

Nebraska Center for Virology: Faculty Publications

Here, we report the complete genome sequence of an Indian strain of chikungunya virus isolated from an infected patient from Hyderabad, Andhra Pradesh, India, during a massive outbreak in 2005–2006. The genome length spans 11,811 nucleotides and has a poly(A) tail of 29 residues at the 3′ end.

Combination Therapy Of Ido1 Inhibition And Anti-Pd1 Mediates Anti-Tumor Immunity By Promoting Memory Immunity Development And Cytotoxicity Of Γδ T And Nk Cells Via Il-2 Signaling And By Overcoming Pro-Tumor Effects Of Tgf-Β Signaling, Hyuk Jee

Dartmouth College Master’s Theses

Cutaneous melanoma is the most aggressive form of skin cancer even though it takes only about 1% of all skin cancers. Even among all cutaneous melanomas, NRAS-mutant melanoma is more aggressive than any other, and about 10-25% of all cutaneous melanoma cases have mutations in NRAS. NRAS is a member of the RAS family of proto-oncogenic GTPase proteins, and it plays a key role in signal transduction pathways responsible for cellular survival, proliferation, and metabolism. Immunotherapy is the first line of defense against NRAS-mutant melanoma because, despite tremendous efforts made for decades, it has not been successful to develop small …