Medical Cell Biology Commons^™

Promotion Of Hiv Clearance By Sensitization Of Hiv Reservoirs To Cell Death, Min Li, Baichao Sun, Jing Dong, Jian-Rong Li, Laurie J Minze, Min Chen, Chao Cheng, Jin Wang

Faculty, Staff and Students Publications

Introduction: HIV integrates its proviral DNA into the host genome to establish persistent infection. To promote HIV clearance, we have designed an approach for selective elimination of host cells harboring replication-competent HIV (SECH), through inhibition of autophagy and anti-apoptotic molecules during viral reactivation. SECH approach can clear HIV-infected cells in approximately 50% humanized mice. However, the mechanisms for the resistance of reservoirs to depletion in mice with failure in HIV clearance are unclear.

Methods: We have performed single cell transcriptome analyses of HIV-infected T cells that escaped the treatments, in order to identify cellular pathways that could be targeted to …

Reliable Rna-Seq Analysis From Ffpe Specimens As A Means To Accelerate Cancer-Related Health Disparities Research, Mitchell J Frederick, Dannelys Perez-Bello, Pedram Yadollahi, Patricia Castro, Alan Frederick, Andrew Frederick, Rashid A Osman, Fonma Essien, Imelda Yebra, Ashley Hamlin, Thomas J Ow, Heath D Skinner, Vlad C Sandulache

Faculty, Staff and Students Publications

Whole transcriptome sequencing (WTS/ RNA-Seq) is a ubiquitous tool for investigating cancer biology. RNA isolated from frozen sources limits possible studies for analysis of associations with phenotypes or clinical variables requiring long-term follow-up. Although good correlations are reported in RNA-Seq data from paired frozen and formalin fixed paraffin embedded (FFPE) samples, uncertainties regarding RNA quality, methods of extraction, and data reliability are hurdles to utilization of archival samples. We compared three different platforms for performing RNA-seq using archival FFPE oropharyngeal squamous carcinoma (OPSCC) specimens stored up to 20 years, as part of an investigation of transcriptional profiles related to health …

Tobacco Exposure Linked To Warthin’S Tumor Being The Most Common Benign Parotid Neoplasm In Veterans: A Retrospective Cohort Study, Louis Abarca, Linda K Green, Ray Y Wang, Vlad C Sandulache, David J Hernandez

Faculty, Staff and Students Publications

Objective: Parotid gland neoplasms account for a large proportion of benign salivary gland tumors, with pleomorphic adenomas (PA) being the most common in the civilian population, followed by Warthin's tumor (WT). However, the distinct risk profiles of Veterans significantly influence the incidence and prevalence of salivary gland neoplasms. We investigated the diagnostic and management algorithms for benign parotid gland neoplasms in Veterans.

< >Methods: Retrospective cohort study. Descriptive statistics were calculated using Microsoft Excel. Categorical variables were compared using chi square tests, and were reported with 95% confidence intervals, with statistical significance set at P <  .05.

Results: The study included 158 patients …

Relationships Of Personality Traits With The Taxonomic Composition Of The Gut Microbiome Among Psychiatric Inpatients, William Orme, Sandra L Grimm, Divya S N Vella, J Christopher Fowler, B Christopher Frueh, Benjamin L Weinstein, Joseph Petrosino, Cristian Coarfa, Alok Madan

Faculty, Staff and Students Publications

Objective: Through the brain-gut-microbiome axis, myriad psychological functions that affect behavior share a dynamic, bidirectional relationship with the intestinal microbiome. Little is known about the relationship between personality-a stable construct that influences social- and health-related behaviors-and the bacterial ecosystem. The authors of this exploratory study examined the relationship between general and maladaptive personality traits and the composition of the gut microbiome.

Methods: In total, 105 psychiatric inpatients provided clinical data and fecal samples. Personality traits were measured with the five-factor model of personality, the Structured Clinical Interview for DSM-IV Axis II Personality Disorders, and the Personality Inventory for DSM-5; 16S …

Xanthine Oxidoreductase, Uric Acid, And Iron Homeostasis: Discovering A Therapeutic Vulnerability In Breast Cancer, Matthew G. Chapa

Graduate Theses, Dissertations, and Problem Reports (ETD)

Breast cancer remains the most frequently diagnosed malignancy and the leading cause of cancer related deaths in women. This is primarily due to distant metastases, which highlight the necessity to understand factors that contribute to breast cancer progression. Emerging evidence associates decreased tumor xanthine oxidoreductase (XOR) expression with a poorer prognosis, increased recurrence, and a more aggressive phenotype. While healthy liver, intestines, kidneys, and breast tissue have robust XOR expression and activity, there is a tendency for this to be ablated in carcinogenesis. This dissertation investigates XOR's role in breast cancer and identifies its product, uric acid (UA), as possessing …

Pathology Discovered In The “First Patient” Can Be The Silent Teacher Of Self-Directed Learning, Mary Leupold, Daniel Topping, R. John Cork, Robin Mcgoey, Guenevere Rae

School of Medicine Faculty Publications

Pathology found during cadaveric dissection has been used to model integrative teaching methods for medical students at several institutions. Recent evidence has shown that pathology found during dissection can be used in the design of self-directed learning (SDL) activities with standards that are difficult to meet. This study presents a novel method for providing formative feedback, one of the most challenging aspects for LCME accreditation of SDL activities. Three practitioners (two board certified pathologists and one board certified family physician) reviewed and rated pathological findings during routine dissection by first year medical students in the gross anatomy laboratory in New …

Decoding Ras Mutations In Thyroid Cancer: A Meta-Analysis Unveils Specific Links To Distant Metastasis And Increased Mortality, Isabel Riccio, Alexandra Laforteza, Madeleine B. Landau, Mohammad H. Hussein, Joshua Linhuber, Jonathan Staav, Peter P. Issa, Eman A. Toraih, Emad Kandil

School of Medicine Faculty Publications

Background/objectives: RAS mutations are common in thyroid cancer, but their impact on clinical outcomes remains controversial. This study aimed to evaluate the prevalence of RAS mutations in thyroid cancer and their association with various clinical and pathological features. Methods: We conducted a systematic review and meta-analysis of studies reporting on RAS mutations in thyroid cancer. Both one-arm and pairwise meta-analyses were performed to compare outcomes between RAS-mutated (RAS+) and wild-type (RAS-) thyroid cancers. Results: Our analysis included 2552 thyroid cancer patients from 17 studies. The overall prevalence of RAS mutations was 35.4 % (95 % CI: 22.7 %–50.7 %). NRAS …

Large-Scale Crispr/Cas9 Deletions Within The Wfdc Gene Cluster Uncover Gene Functionality And Critical Roles In Mammalian Reproduction, Katarzyna Kent, Kaori Nozawa, Rachel Parkes, Laura Dean, Frey Daniel, Mei Leng, Antrix Jain, Anna Malovannaya, Martin M Matzuk, Thomas X Garcia

Faculty, Staff and Students Publications

Despite 96 million years of evolution separating humans and rodents, 11 closely related reproductive tract-specific genes in humans—SPINT3, WFDC6, EPPIN, WFDC8, WFDC9, WFDC10A, WFDC11, WFDC10B, WFDC13, SPINT4, and WFDC3—and the 13 reproductive tract-specific orthologous genes in mice, form highly conserved syntenic gene clusters indicative of conserved, combined critical functions. Further, despite significant progress toward a nonhormonal male contraceptive targeting the protein encoded by one of these genes, epididymal peptidase inhibitor (EPPIN), and associations found between mutations in EPPIN and an increased risk of male infertility, neither EPPIN nor …

Uba1 Inhibition Sensitizes Cancer Cells To Parp Inhibitors, Sharad Awasthi, Lacey E Dobrolecki, Christina Sallas, Xudong Zhang, Yang Li, Sima Khazaei, Sumanta Ghosh, Collene R Jeter, Jinsong Liu, Gordon B Mills, Shannon N Westin, Michael T Lewis, Weiyi Peng, Anil K Sood, Timothy A Yap, S Stephen Yi, Daniel J Mcgrail, Nidhi Sahni

Faculty, Staff and Students Publications

Therapeutic strategies targeting the DNA damage response, such as poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi), have revolutionized cancer treatment in tumors deficient in homologous recombination (HR). However, overcoming innate and acquired resistance to PARPi remains a significant challenge. Here, we employ a genome-wide CRISPR knockout screen and discover that the depletion of ubiquitin-activating enzyme E1 (UBA1) enhances sensitivity to PARPi in HR-proficient ovarian cancer cells. We show that silencing or pharmacological inhibition of UBA1 sensitizes multiple cell lines and organoid models to PARPi. Mechanistic studies uncover that UBA1 inhibition not only impedes HR repair to sensitize cells to PARP inhibition …

Development Of A Ripk1 Degrader To Enhance Antitumor Immunity, Xin Yu, Dong Lu, Xiaoli Qi, Rishi Ram Paudel, Hanfeng Lin, Bryan L Holloman, Feng Jin, Longyong Xu, Lang Ding, Weiyi Peng, Meng C Wang, Xi Chen, Jin Wang

Faculty, Staff and Students Publications

The scaffolding function of receptor interacting protein kinase 1 (RIPK1) confers intrinsic and extrinsic resistance to immune checkpoint blockades (ICBs) and emerges as a promising target for improving cancer immunotherapies. To address the challenge posed by a poorly defined binding pocket within the intermediate domain of RIPK1, here we harness proteolysis targeting chimera (PROTAC) technology to develop a RIPK1 degrader, LD4172. LD4172 exhibits potent and selective RIPK1 degradation both in vitro and in vivo. Degradation of RIPK1 by LD4172 triggers immunogenic cell death, enhances tumor-infiltrating lymphocyte responses, and sensitizes tumors to anti-PD1 therapy in female C57BL/6J mice. This work reports …

Comparative Efficacy, Safety, And Oncological Outcomes Of Percutaneous Thermal And Chemical Ablation Modalities For Recurrent Metastatic Cervical Lymphadenopathy From Thyroid Cancer, Eman A. Toraih, Siva Paladugu, Rami M. Elshazli, Mohammad M. Hussein, Hassan Malik, Humza Pirzadah, Ahmed Abdelmaksoud, Salem I. Noureldine, Emad Kandil

School of Medicine Faculty Publications

Background: Thermal and chemical ablation techniques may consolidate recurrent metastatic cervical lymph nodes as alternatives to repeat neck dissection in thyroid cancer patients. This meta-analysis aims to compare the efficacy and safety across modalities. Methods: Four databases were searched for studies on radiofrequency (RFA), microwave (MWA), laser (LA), and ethanol ablation (EA) treating metastatic cervical nodes from thyroid cancer. The outcomes analyzed included treatment response, oncologic control, and complications. Random effects meta-analytical pooling was conducted. Results: There were 25 studies (n = 1061 nodes) examining the four ablation methods. Patients showed comparable baseline characteristics and initial lymph node sizes ranging …

Unraveling The Link Between Language Barriers And Cancer Risk, Eman A. Toraih, Mohammad H. Hussein, Manal S. Malik, Alaa N. Malik, Emad Kandil, Manal S. Fawzy

School of Medicine Faculty Publications

Purpose: Clear patient communication with the physician is an integral aspect of cancer treatment and successful health outcomes. Previous research has shown improved cancer screening in cases of patient navigator assistance to limited English proficient patients, but no research has analyzed the relationship between language isolation and cancer incidence rates in the United States. Methods: Using state-level data from the United States Census Bureau and the National Cancer Institute, we analyzed the correlations between language isolation and age-adjusted incidence rates across 19 different invasive cancers. Results: A complex relationship between language isolation and cancer incidence rates was found. States such …

Single-Molecule Studies Reveal The Off-Pathway Early Paused State Intermediates As A Target Of Streptolydigin Inhibition Of Rna Polymerase And Its Dramatic Enhancement By Gre Factors, Anatolii Arseniev, Mikhail Panfilov, Georgii Pobegalov, Alina Potyseva, Polina Pavlinova, Maria Yakunina, Jookyung Lee, Sergei Borukhov, Konstantin Severinov, Mikhail Khodorkovskii

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Antibiotic streptolydigin (Stl) inhibits bacterial transcription by blocking the trigger loop folding in the active center of RNA polymerase (RNAP), which is essential for catalysis. We use acoustic force spectroscopy to characterize the dynamics of transcription elongation in ternary elongation complexes (ECs) of RNAP in the presence of Stl at a single-molecule level. We found that Stl induces long-lived stochastic pauses while the instantaneous velocity of transcription between the pauses is unaffected. Stl enhances the short-lived pauses associated with an off-pathway early paused state intermediates of the RNAP nucleotide addition cycle. Unexpectedly, we found that transcript cleavage factors GreA and …

Amniotic Fluid-Derived Stem Cells: Potential Factories Of Natural And Mimetic Strategies For Congenital Malformations, Cristiane S R Fonteles, Julia Enterria-Rosales, Ying Lin, John W Steele, Ramiro A Villarreal-Leal, Jing Xiao, Daniel I Idowu, Beck Burgelin, Bogdan J Wlodarczyk, Richard H Finnell, Bruna Corradetti

Faculty, Staff and Students Publications

BACKGROUND: Mesenchymal stem cells (MSCs) derived from gestational tissues offer a promising avenue for prenatal intervention in congenital malformations although their application is hampered by concerns related to cellular plasticity and the need for invasive, high-risk surgical procedures. Here, we present naturally occurring exosomes (EXOs) isolated from amniotic fluid-derived MSCs (AF-MSCs) and their mimetic analogs (MIMs) as viable, reproducible, and stable alternatives. These nanovesicles present a minimally invasive therapeutic option, addressing the limitations of MSC-based treatments while retaining therapeutic efficacy.

METHODS: MIMs were generated from AF-MSCs by combining sequential filtration steps through filter membranes with different porosity and size exclusion …

Sk609, A Novel Dopamine D3 Receptor Agonist And Norepinephrine Transporter Blocker With Putative Pro-Cognitive Actions, Does Not Induce Psychostimulant-Like Increases In Risky Choice During Probabilistic Discounting, Christopher P. Knapp, Brooke Fallon, Sandhya Kortagere, Barry D. Waterhouse, Stan B Floresco, Rachel L Navarra

Rowan-Virtua School of Osteopathic Medicine Departmental Research

RATIONALE: Psychostimulants, such as amphetamine (AMPH) and methylphenidate (MPH), non-selectively elevate extracellular concentrations of the catecholamine neurotransmitters, dopamine (DA) and norepinephrine (NE), and are common pharmacological strategies used to improve prefrontal cortex (PFC)-dependent cognitive dysfunction. However, this approach can be problematic given AMPH has been shown to increase preference for risky choices in a rodent assay of risk/reward decision making. SK609 is a novel NE reuptake blocker that selectively activates DA D3 receptors without affinity for the DA transporter. SK609 has been shown to improve cognitive performance without increasing psychostimulant-like spontaneous locomotor activity, suggesting SK609 may benefit neurocognitive function without …

Chemogenetic Neuronal Silencing Decouples C-Jun Activation From Cell Death In The Temporal Cortex, Caleb A Wood, Preethi Somasundaram, Jacob M Dundee, Melissa A Rudy, Trent A Watkins, Joanna L Jankowsky

Faculty, Staff and Students Publications

Initial symptoms of neurodegenerative diseases are often defined by the loss of the most vulnerable neural populations specific to each disorder. In the early stages of Alzheimer's disease, vulnerable circuits in the temporal lobe exhibit diminished activity prior to overt degeneration. It remains unclear whether these functional changes contribute to regional vulnerability or are simply a consequence of pathology. We previously found that entorhinal neurons in the temporal cortex undergo cell death following transient suppression of electrical activity, suggesting a causal role for activity disruption in neurodegeneration. Here we demonstrate that electrical arrest of this circuit stimulates the injury-response transcription …

Bst2 Facilitates Activation Of Hematopoietic Stem Cells Through Erk Signaling, Marcus A Florez, Apoorva Thatavarty, Duy T Le, Holly A Hill, Youngjae Jeong, Brian M Ho, Pawel Kus, Trisha K Wathan, Bailee N Kain, Shixia Huang, Dongsu Park, Katherine Y King

Faculty, Staff and Students Publications

The proinflammatory cytokine interferon-gamma (IFNγ) is upregulated in a variety of infections and contributes to bone marrow failure through hematopoietic stem cell (HSC) activation and subsequent exhaustion. The cell surface protein, bone marrow stromal antigen 2 (BST2), is a key mediator of this process, as it is induced upon interferon stimulation and required for interferon-dependent HSC activation. To identify the mechanism by which BST2 promotes interferon-dependent HSC activation, we evaluated its role in niche localization, immune cell function, lipid raft formation, and intracellular signaling. Our studies indicated that knock out (KO) of BST2 in a murine model does not disrupt …

Association Between Microsatellite Instability Status, Clinicopathological Features And Mitochondrial Dna Amplification In Patients With Colorectal Cancer, Junmi Lu, Hong Tan, Tao Guo, Xi Chen, Zhongyi Tong

Faculty, Staff and Students Publications

The relationship between BRAF-V600E mutations, mitochondrial DNA amplification and microsatellite instability-high (MSI-H) in colorectal cancer (CRC) has yet to be fully elucidated. The aim of the present study was to assess the association between the MSI status and BRAF-V600E gene mutations/clinicopathological features/mitochondrial DNA amplification in CRC. A non-interventional study analysis was performed using the clinicopathological features of 455 patients with CRC. Immunohistochemistry was used to evaluate four mismatch repair proteins (MutS homolog 2, MutS homolog 6, MutL homolog 1 and postmeiotic segregation increased 2), Ki-67 index, and programmed cell death protein 1 (PD-1) and programmed cell death-ligand 1 (PD-L1) expression. …

Mtor Maintains Endothelial Cell Integrity To Limit Lung Vascular Injury, Michelle Warren Millar, Rauf A Najar, Spencer A Slavin, Mohammad Shadab, Imran Tahir, Zahra Mahamed, Xin Lin, Jun-Ichi Abe, Terry W Wright, David A Dean, Fabeha Fazal, Arshad Rahman

Faculty, Staff and Student Publications

The functional and structural integrity of the endothelium is essential for vascular homeostasis. Loss of barrier function in quiescent and migratory capacity in proliferative endothelium causes exuberant vascular permeability, a cardinal feature of many inflammatory diseases including acute lung injury (ALI). However, the signals governing these fundamental endothelial cell (EC) functions are poorly understood. Here, we identify mechanistic target of rapamycin (MTOR) as an important link in preserving the barrier integrity and migratory/angiogenic responses in EC and preventing lung vascular injury and mortality in mice. Knockdown of MTOR in EC altered cell morphology, impaired proliferation and migration, and increased endocytosis …

Space: An Open-Source, Single-Cell Analysis Of Cell Painting Data, Fabio Stossi, Pankaj K Singh, Michela Marini, Kazem Safari, Adam T Szafran, Alejandra Rivera Tostado, Christopher D Candler, Maureen G Mancini, Elina A Mosa, Michael J Bolt, Demetrio Labate, Michael A Mancini

Faculty, Staff and Students Publications

Phenotypic profiling by high throughput microscopy, including Cell Painting, has become a leading tool for screening large sets of perturbations in cellular models. To efficiently analyze this big data, available open-source software requires computational resources usually not available to most laboratories. In addition, the cell-to-cell variation of responses within a population, while collected and analyzed, is usually averaged and unused. We introduce SPACe (Swift Phenotypic Analysis of Cells), an open-source platform for analysis of single-cell image-based morphological profiles produced by Cell Painting. We highlight several advantages of SPACe, including processing speed, accuracy in mechanism of action recognition, reproducibility across biological …

Camkk2: Bridging The Gap Between Ca2+ Signaling And Energy-Sensing, Luke M Mcaloon, Abbey G Muller, Kevin Nay, Eudora L Lu, Benoit Smeuninx, Anthony R Means, Mark A Febbraio, John W Scott

Faculty, Staff and Students Publications

Calcium (Ca2+) ions are ubiquitous and indispensable signaling messengers that regulate virtually every cell function. The unique ability of Ca2+ to regulate so many different processes yet cause stimulus specific changes in cell function requires sensing and decoding of Ca2+ signals. Ca2+-sensing proteins, such as calmodulin, decode Ca2+ signals by binding and modifying the function of a diverse range of effector proteins. These effectors include the Ca2+-calmodulin dependent protein kinase kinase-2 (CaMKK2) enzyme, which is the core component of a signaling cascade that plays a key role in important physiological and pathophysiological processes, including brain function and cancer. In addition …

Sample Multiplexing For Retinal Single-Cell Rna Sequencing, Justin Ma, Ting-Kuan Chu, Maria Polo-Prieto, Yong H Park, Yumei Li, Rui Chen, Graeme Mardon, Benjamin J Frankfort, Nicholas M Tran

Faculty, Staff and Students Publications

Rare cell populations can be challenging to characterize using microfluidic single-cell RNA sequencing (scRNA-seq) platforms. Typically, the population of interest must be enriched and pooled from multiple biological specimens for efficient collection. However, these practices preclude the resolution of sample origin together with phenotypic data and are problematic in experiments in which biological or technical variation is expected to be high (e.g., disease models, genetic perturbation screens, or human samples). One solution is sample multiplexing whereby each sample is tagged with a unique sequence barcode that is resolved bioinformatically. We have established a scRNA-seq sample multiplexing pipeline for mouse retinal …

The Relationship Between Spectral Signals And Retinal Sensitivity In Dendrobatid Frogs, Whitney G. Walkowski, Corinne L. Richards-Zawacki, William C. Gordon, Nicolas G. Bazan, Hamilton E. Farris

School of Graduate Studies Faculty Publications

Research on visually driven behavior in anurans has often focused on Dendrobatoidea, a clade with extensive variation in skin reflectance, which is perceived to range from cryptic to conspicuous coloration. Because these skin patterns are important in intraspecific and interspecific communication, we hypothesized that the visual spectral sensitivity of dendrobatids should vary with conspecific skin spectrum. We predicted that the physiological response of frog retinas would be tuned to portions of the visible light spectrum that match their body reflectance. Using wavelength-specific electroretinograms (ERGs; from 350-650 nm), spectrometer measurements, and color-calibrated photography of the skin, we compared retinal sensitivity and …

Automatically Extracting Social Determinants Of Health For Suicide: A Narrative Literature Review, Annika M Schoene, Suzanne Garverich, Iman Ibrahim, Sia Shah, Benjamin Irving, Clifford C Dacso

Faculty, Staff and Students Publications

Suicide is a complex phenomenon that is often not preceded by a diagnosed mental health condition, therefore making it difficult to study and mitigate. Artificial Intelligence has increasingly been used to better understand Social Determinants of Health factors that influence suicide outcomes. In this review we find that many studies use limited SDoH information and minority groups are often underrepresented, thereby omitting important factors that could influence risk of suicide.

Activation Of A Gpcr, Orl1 Receptor: A Novel Therapy To Prevent Heart Failure Progression, Saliha S Pathan, Aarthi Pugazenthi, Beverly R E A Dixon, Theodore G Wensel, Todd K Rosengart, Megumi Mathison

Faculty, Staff and Students Publications

The number of ischemic heart failure (HF) patients is growing dramatically worldwide. However, there are at present no preventive treatments for HF. Our previous study showed that Gata4 overexpression improved cardiac function after myocardial infarction in rat hearts. We also found that Gata4 overexpression significantly increased the expression of a Pnoc gene, an endogenous ligand for the cell membrane receptor ORL1. We hypothesized that the activation of the ORL1 receptor would suppress HF in a rat ischemic heart model. Adult Sprague Dawley rats (8 weeks old, six males and six females) underwent left anterior descending coronary artery ligation. Three weeks …

Nerve Injury Inhibits Oprd1 And Cnr1 Transcription Through Rest In Primary Sensory Neurons, Ashok Subedi, Asieh Etemad, Aadhya Tiwari, Yuying Huang, Biji Chatterjee, Samantha M Mcleod, Yungang Lu, Diangelo Gonzalez, Krishna Ghosh, Mario Sirito, Sanjay K Singh, Elisa Ruiz, Sandra L Grimm, Cristian Coarfa, Hui-Lin Pan, Sadhan Majumder

Faculty, Staff and Students Publications

The transcription repressor REST in the dorsal root ganglion (DRG) is upregulated by peripheral nerve injury and promotes the development of chronic pain. However, the genes targeted by REST in neuropathic pain development remain unclear. The expression levels of four opioid receptor genes (Oprm1, Oprd1, Oprl1 and Oprk1) and the cannabinoid CB1 receptor (Cnr1) gene in the DRG regulate nociception. In this study, we determined the role of REST in controlling their expression in the DRG induced by spared nerve injury (SNI). SNI induced chronic pain hypersensitivity in wild-type mice and was accompanied by increased levels of Rest transcript and …

Mechanisms Of Extracellular Vesicle Uptake And Implications For The Design Of Cancer Therapeutics, Stephanie R Jackson Cullison, Joseph P Flemming, Kubra Karagoz, Peter J Wermuth, Mỹ G Mahoney

Rowan-Virtua School of Osteopathic Medicine Departmental Research

The translation of pre-clinical anti-cancer therapies to regulatory approval has been promising, but slower than hoped. While innovative and effective treatments continue to achieve or seek approval, setbacks are often attributed to a lack of efficacy, failure to achieve clinical endpoints, and dose-limiting toxicities. Successful efforts have been characterized by the development of therapeutics designed to specifically deliver optimal and effective dosing to tumour cells while minimizing off-target toxicity. Much effort has been devoted to the rational design and application of synthetic nanoparticles to serve as targeted therapeutic delivery vehicles. Several challenges to the successful application of this modality as …

Anti-Egfr Aptamer Exhibits Direct Anti-Cancer Effects In Nsclc Cells Harboring Egfr L858r Mutations, Brian J. Thomas, Sania Z. Awan, Trupti Joshi, Mark A. Daniels, David Porciani, Donald H. Burke

Biomedical Sciences

Non-small cell lung cancer (NSCLC) adenocarcinoma (LUAD) is a leading cause of death worldwide. Activating mutations in the tyrosine kinase domain of the oncogene epidermal growth factor receptor (EGFR) are responsible for ~10–50% of all LUAD cases. Although tyrosine kinase inhibitors (TKIs) have been effective in prolonging patient survival and quality of life, acquired resistance and disease progression are inevitable, presenting a clear unmet need for alternative or adjuvant therapeutics. Here we show that an anti-EGFR aptamer (EGFRapt) decreases viability and tumor growth of LUAD cell lines harboring the L858R ± T790M mutation in EGFR. Additionally, we elucidate …

Small And Long Non-Coding Rna Analysis For Humantrophoblast-Derived Extracellular Vesicles And Their Effect On The Transcriptome Profile Of Human Neural Progenitor Cells, Jessica A. Kinkade, Pallav Singh, Mohit Verma, Teka Khan, Toshihoko Ezashi, Nathan J. Bivens, R. Michael Roberts, Trupti Joshi, Cheryl S. Rosenfeld

Biomedical Sciences

In mice, the fetal brain is dependent upon the placenta for factors that guide its early development. This linkage between the two organs has given rise to the term, the placenta–brain axis. A similar interrelationship between the two organs may exist in humans. We hypothesize that extracellular vesicles (EVs) released from placental trophoblast (TB) cells transport small RNA and other informational biomolecules from the placenta to the brain where their contents have pleiotropic effects. Here, EVs were isolated from the medium in which human trophoblasts (TBs) had been differentiated in vitro from induced pluripotent stem cells (iPSC) and from cultured …

Bcl-Xl Is Translocated To The Nucleus Via Ctbp2 To Epigenetically Promote Metastasis, Tiantian Zhang, Sha Li, Yingcai Adrian Tan, Xiang Chen, Cheryl Zhang, Zhengming Chen, Bikash Mishra, Joseph Hyungjoon Na, Soyoung Choi, Sandra J Shin, Priyadarshan Damle, Kranthi Kumar Chougoni, Steven R Grossman, Dunrui Wang, Xuejun Jiang, Yi Li, Erika Hissong, Yao-Tseng Chen, Jenny Z Xiang, Yi-Chieh Nancy Du

Faculty, Staff and Students Publications

Nuclear Bcl-xL is found to promote cancer metastasis independently of its mitochondria-based anti-apoptotic activity. How Bcl-xL is translocated into the nucleus and how nuclear Bcl-xL regulates histone H3 trimethyl Lys4 (H3K4me3) modification have yet to be understood. Here, we report that C-terminal Binding Protein 2 (CtBP2) binds to Bcl-xL via its N-terminus and translocates Bcl-xL into the nucleus. Knockdown of CtBP2 by shRNA decreases the nuclear portion of Bcl-xL and reverses Bcl-xL-induced invasion and metastasis in mouse models. Furthermore, knockout of CtBP2 not only reduces the nuclear portion of Bcl-xL but also suppresses Bcl-xL transcription. The binding between Bcl-xL and …