Digital Commons Network^™

The Neuroimmune Regulation And Potential Therapeutic Strategies Of Optic Pathway Glioma, Khushboo Irshad, Yu-Kai Huang, Paul Rodriguez, Jung Lo, Benjamin E Aghoghovwia, Yuan Pan, Kun-Che Chang

Faculty, Staff and Student Publications

Optic pathway glioma (OPG) is one of the causes of pediatric visual impairment. Unfortunately, there is as yet no cure for such a disease. Understanding the underlying mechanisms and the potential therapeutic strategies may help to delay the progression of OPG and rescue the visual morbidities. Here, we provide an overview of preclinical OPG studies and the regulatory pathways controlling OPG pathophysiology. We next discuss the role of microenvironmental cells (neurons, T cells, and tumor-associated microglia and macrophages) in OPG development. Last, we provide insight into potential therapeutic strategies for treating OPG and promoting axon regeneration.

The Gut Microbiome As A Biomarker And Therapeutic Target In Hepatocellular Carcinoma, Betul Gok Yavuz, Saumil Datar, Shadi Chamseddine, Yehia I Mohamed, Michael Lapelusa, Sunyoung S Lee, Zishuo Ian Hu, Eugene J Koay, Hop S Tran Cao, Prasun Kumar Jalal, Carrie Daniel-Macdougall, Manal Hassan, Dan G Duda, Hesham M Amin, Ahmed O Kaseb

Faculty, Staff and Student Publications

The microbiome is pivotal in maintaining health and influencing disease by modulating essential inflammatory and immune responses. Hepatocellular carcinoma (HCC), ranking as the third most common cause of cancer-related fatalities globally, is influenced by the gut microbiome through bidirectional interactions between the gut and liver, as evidenced in both mouse models and human studies. Consequently, biomarkers based on gut microbiota represent promising non-invasive tools for the early detection of HCC. There is a growing body of evidence suggesting that the composition of the gut microbiota may play a role in the efficacy of immunotherapy in different types of cancer; thus, …

Multiphoton In Vivo Microscopy Of Embryonic Thrombopoiesis Reveals The Generation Of Platelets Through Budding, Huan Liu, Hellen Ishikawa-Ankerhold, Julia Winterhalter, Michael Lorenz, Mykhailo Vladymyrov, Steffen Massberg, Christian Schulz, Mathias Orban

Faculty, Staff and Student Publications

Platelets are generated by specialized cells called megakaryocytes (MKs). However, MK's origin and platelet release mode have remained incompletely understood. Here, we established direct visualization of embryonic thrombopoiesis in vivo by combining multiphoton intravital microscopy (MP-IVM) with a fluorescence switch reporter mouse model under control of the platelet factor 4 promoter (Pf4CreRosa26mTmG). Using this microscopy tool, we discovered that fetal liver MKs provide higher thrombopoietic activity than yolk sac MKs. Mechanistically, fetal platelets were released from MKs either by membrane buds or the formation of proplatelets, with the former constituting the key process. In E14.5 c-Myb-deficient …

High-Fat Diet, But Not Duration Of Lactation, Increases Mammary Gland Lymphatic Vessel Function And Subsequent Growth Of Inflammatory Breast Cancer Cells, Wintana Balema, Janelle Morton, Richard A Larson, Li Li, Fred Christian Velasquez, Natalie W Fowlkes, Savitri Krishnamurthy, Bisrat G Debeb, Eva Sevick-Muraca, Wendy A Woodward

Faculty, Staff and Student Publications

Inflammatory breast cancer (IBC) presents as rapid-onset swelling and breast skin changes caused by tumor emboli in the breast and breast skin lymphatics. IBC has been linked with obesity and duration of breastfeeding, but how these factors affect IBC tumor progression is not clear. We modeled the simultaneous effects of diet and weaning in mice on in vivo lymphatic function; on IBC tumor growth; and on aspects of the mammary gland microenvironment before and after IBC (SUM149) xenograft inoculation. We hypothesized that weaning status and diet would have synergistic effects on lymphatic function and the breast microenvironment to enhance IBC …

Epigenomic Signature Of Major Congenital Heart Defects In Newborns With Down Syndrome, Julia S Mouat, Shaobo Li, Swe Swe Myint, Benjamin I Laufer, Philip J Lupo, Jeremy M Schraw, John P Woodhouse, Adam J De Smith, Janine M Lasalle

Faculty, Staff and Students Publications

BACKGROUND: Congenital heart defects (CHDs) affect approximately half of individuals with Down syndrome (DS), but the molecular reasons for incomplete penetrance are unknown. Previous studies have largely focused on identifying genetic risk factors associated with CHDs in individuals with DS, but comprehensive studies of the contribution of epigenetic marks are lacking. We aimed to identify and characterize DNA methylation differences from newborn dried blood spots (NDBS) of DS individuals with major CHDs compared to DS individuals without CHDs.

METHODS: We used the Illumina EPIC array and whole-genome bisulfite sequencing (WGBS) to quantitate DNA methylation for 86 NDBS samples from the …

Pls3 Missense Variants Affecting The Actin-Binding Domains Cause X-Linked Congenital Diaphragmatic Hernia And Body-Wall Defects, Florence Petit, Mauro Longoni, Julie Wells, Richard S Maser, Eric L Bogenschutz, Matthew J Dysart, Hannah T M Contreras, Frederic Frénois, Barbara R Pober, Robin D Clark, Philip F Giampietro, Hilger H Ropers, Hao Hu, Maria Loscertales, Richard Wagner, Xingbin Ai, Harrison Brand, Anne-Sophie Jourdain, Marie-Ange Delrue, Brigitte Gilbert-Dussardier, Louise Devisme, Boris Keren, David J Mcculley, Lu Qiao, Rebecca Hernan, Julia Wynn, Tiana M Scott, Daniel G Calame, Zeynep Coban-Akdemir, Patricia Hernandez, Andres Hernandez-Garcia, Hagith Yonath, James R Lupski, Yufeng Shen, Wendy K Chung, Daryl A Scott, Carol J Bult, Patricia K Donahoe, Frances A High

Faculty, Staff and Student Publications

Congenital diaphragmatic hernia (CDH) is a relatively common and genetically heterogeneous structural birth defect associated with high mortality and morbidity. We describe eight unrelated families with an X-linked condition characterized by diaphragm defects, variable anterior body-wall anomalies, and/or facial dysmorphism. Using linkage analysis and exome or genome sequencing, we found that missense variants in plastin 3 (PLS3), a gene encoding an actin bundling protein, co-segregate with disease in all families. Loss-of-function variants in PLS3 have been previously associated with X-linked osteoporosis (MIM: 300910), so we used in silico protein modeling and a mouse model to address these seemingly disparate clinical …

An Intrinsically Disordered Region Controlling Condensation Of A Circadian Clock Component And Rhythmic Transcription In The Liver, Kun Zhu, Isaac J Celwyn, Dongyin Guan, Yang Xiao, Xiang Wang, Wenxiang Hu, Chunjie Jiang, Lan Cheng, Rafael Casellas, Mitchell A Lazar

Faculty, Staff and Students Publications

Circadian gene transcription is fundamental to metabolic physiology. Here we report that the nuclear receptor REV-ERBα, a repressive component of the molecular clock, forms circadian condensates in the nuclei of mouse liver. These condensates are dictated by an intrinsically disordered region (IDR) located in the protein's hinge region which specifically concentrates nuclear receptor corepressor 1 (NCOR1) at the genome. IDR deletion diminishes the recruitment of NCOR1 and disrupts rhythmic gene transcription in vivo. REV-ERBα condensates are located at high-order transcriptional repressive hubs in the liver genome that are highly correlated with circadian gene repression. Deletion of the IDR disrupts transcriptional …

Gut Microbiota Aggravates Neutrophil Extracellular Traps-Induced Pancreatic Injury In Hypertriglyceridemic Pancreatitis, Guanqun Li, Liwei Liu, Tianqi Lu, Yuhang Sui, Can Zhang, Yongwei Wang, Tao Zhang, Yu Xie, Peng Xiao, Zhongjie Zhao, Chundong Cheng, Jisheng Hu, Hongze Chen, Dongbo Xue, Hua Chen, Gang Wang, Rui Kong, Hongtao Tan, Xuewei Bai, Zhibo Li, Florencia Mcallister, Le Li, Bei Sun

Faculty, Staff and Student Publications

Hypertriglyceridemic pancreatitis (HTGP) is featured by higher incidence of complications and poor clinical outcomes. Gut microbiota dysbiosis is associated with pancreatic injury in HTGP and the mechanism remains unclear. Here, we observe lower diversity of gut microbiota and absence of beneficial bacteria in HTGP patients. In a fecal microbiota transplantation mouse model, the colonization of gut microbiota from HTGP patients recruits neutrophils and increases neutrophil extracellular traps (NETs) formation that exacerbates pancreatic injury and systemic inflammation. We find that decreased abundance of Bacteroides uniformis in gut microbiota impairs taurine production and increases IL-17 release in colon that triggers NETs formation. …

Excitatory Neuron-Specific Suppression Of The Integrated Stress Response Contributes To Autism-Related Phenotypes In Fragile X Syndrome, Mehdi Hooshmandi, Vijendra Sharma, Carolina Thörn Perez, Rapita Sood, Konstanze Krimbacher, Calvin Wong, Kevin C Lister, Alba Ureña Guzmán, Trevor D Bartley, Cecilia Rocha, Gilles Maussion, Emma Nadler, Patricia Margarita Roque, Ilse Gantois, Jelena Popic, Maxime Lévesque, Randal J Kaufman, Massimo Avoli, Elisenda Sanz, Karim Nader, Randi Jenssen Hagerman, Thomas M Durcan, Mauro Costa-Mattioli, Masha Prager-Khoutorsky, Jean-Claude Lacaille, Veronica Martinez-Cerdeno, Jay R Gibson, Kimberly M Huber, Nahum Sonenberg, Christos G Gkogkas, Arkady Khoutorsky

Faculty, Staff and Students Publications

Dysregulation of protein synthesis is one of the key mechanisms underlying autism spectrum disorder (ASD). However, the role of a major pathway controlling protein synthesis, the integrated stress response (ISR), in ASD remains poorly understood. Here, we demonstrate that the main arm of the ISR, eIF2α phosphorylation (p-eIF2α), is suppressed in excitatory but not inhibitory neurons in a mouse model of fragile X syndrome (FXS; Fmr1−/y). We further show that the decrease in p-eIF2α is mediated via activation of the mTORC1. Genetic reduction of p-eIF2α only in excitatory neurons is sufficient to increase general protein synthesis and cause autism-like …

Lung Resident Memory B Cells Maintain Allergic Ige Responses In The Respiratory Tract, Alexander James Nelson

Dissertations

Immunoglobulin E (IgE) is the primary cause of allergic asthma. Allergen-specific IgE can be detected in the airway of allergic asthma patients even in the absence of circulating IgE, suggesting that IgE can be synthesized locally in the respiratory tract. However, the source of IgE-producing B cells, as well as how IgE responses arise and persist at mucosal sites are not fully understood. To address these questions, we modeled allergic asthma in mice by repeated intranasal administration of ragweed pollen and ovalbumin (OVA). We found that allergen exposure induced the production of local IgE in the airway and formation of …

Antimicrobial Resistance And Rational Prescription Practices: Knowledge, Perceptions And Confidence Of Health Profession Interns In Uganda, Shamim Nabidda, Rogers Ssennyonjo, Joseph Atwaru, Andrew Marvin Kanyike, Shiellah Baryayaka, Kennedy Pangholi, Jonans Tusiimire

School of Nursing & Midwifery, East Africa

Background

Antimicrobial resistance (AMR) is significantly driven by misuse and overuse of antibiotics. Graduate health profession interns often prescribe antimicrobials under minimum supervision.

Objectives

This study explored the knowledge, perceptions and confidence of health profession interns in Uganda regarding AMR and rational prescription practices.

Methods

This was a cross-sectional survey employing quantitative techniques carried out between October and November 2022 at six tertiary hospitals in Uganda. Health profession interns including doctors, nurses, midwives and pharmacists were recruited as study participants. Data were collected using online Kobo toolbox software. Data analysis was performed using STATA (StataCorp) version 16. Bivariate analysis and …

An Update On Strategies To Deliver Protein And Peptide Drugs To The Eye, Sai H S Boddu, Devarshi Acharya, Vivek Hala, Harshil Jani, Sonal Pande, Chirag Patel, Moyad Shahwan, Renukuntla Jwala, Ketan M Ranch

Faculty, Staff and Student Publications

In the past few decades, advancements in protein engineering, biotechnology, and structural biochemistry have resulted in the discovery of various techniques that enhanced the production yield of proteins, targetability, circulating half-life, product purity, and functionality of proteins and peptides. As a result, the utilization of proteins and peptides has increased in the treatment of many conditions, including ocular diseases. Ocular delivery of large molecules poses several challenges due to their high molecular weight, hydrophilicity, unstable nature, and poor permeation through cellular and enzymatic barriers. The use of novel strategies for delivering protein and peptides such as glycoengineering, PEGylation, Fc-fusion, chitosan …

Report Of The Assay Guidance Workshop On 3-Dimensional Tissue Models For Antiviral Drug Development, Robert Jordan, Stephanie L Ford-Scheimer, Rodolfo M Alarcon, Anthony Atala, Jeffrey T Borenstein, Kyle R Brimacombe, Sara Cherry, Hans Clevers, Mindy I Davis, Simon G P Funnell, Lee Gehrke, Linda G Griffith, Abigail C Grossman, Thomas Hartung, Donald E Ingber, Nicole C Kleinstreuer, Calvin J Kuo, Emily M Lee, Christine L Mummery, Thames E Pickett, Sasirekha Ramani, Edwin A Rosado-Olivieri, Evi B Struble, Zhengpeng Wan, Mark S Williams, Matthew D Hall, Marc Ferrer, Sarine Markossian

Faculty, Staff and Students Publications

The National Center for Advancing Translational Sciences (NCATS) Assay Guidance Manual (AGM) Workshop on 3D Tissue Models for Antiviral Drug Development, held virtually on 7-8 June 2022, provided comprehensive coverage of critical concepts intended to help scientists establish robust, reproducible, and scalable 3D tissue models to study viruses with pandemic potential. This workshop was organized by NCATS, the National Institute of Allergy and Infectious Diseases, and the Bill and Melinda Gates Foundation. During the workshop, scientific experts from academia, industry, and government provided an overview of 3D tissue models' utility and limitations, use of existing 3D tissue models for antiviral …

Spa-Stocsy: An Automated Tool For Identifying Annotated And Non-Annotated Metabolites In High-Throughput Nmr Spectra, Xu Han, Wanli Wang, Li-Hua Ma, Ismael Ai-Ramahi, Juan Botas, Kevin Mackenzie, Genevera I Allen, Damian W Young, Zhandong Liu, Mirjana Maletic-Savatic

Faculty, Staff and Students Publications

MOTIVATION: Nuclear magnetic resonance spectroscopy (NMR) is widely used to analyze metabolites in biological samples, but the analysis requires specific expertise, it is time-consuming, and can be inaccurate. Here, we present a powerful automate tool, SPatial clustering Algorithm-Statistical TOtal Correlation SpectroscopY (SPA-STOCSY), which overcomes challenges faced when analyzing NMR data and identifies metabolites in a sample with high accuracy.

RESULTS: As a data-driven method, SPA-STOCSY estimates all parameters from the input dataset. It first investigates the covariance pattern among datapoints and then calculates the optimal threshold with which to cluster datapoints belonging to the same structural unit, i.e. the metabolite. …

Intraperitoneal Paclitaxel Is A Safe And Effective Therapeutic Strategy For Treating Mucinous Appendiceal Adenocarcinoma, Ichiaki Ito, Abdelrahman M G Yousef, Saikat Chowdhury, Princess N Dickson, Zahra A Naini, Michael G White, Karianne G Fleten, Kjersti Flatmark, Keith F Fournier, Natalie W Fowlkes, John Paul Shen

Faculty, Staff and Student Publications

Appendiceal adenocarcinomas (AAs) are a rare and heterogeneous mix of tumors for which few preclinical models exist. The rarity of AA has made performing prospective clinical trials difficult, which has partly contributed to AA remaining an orphan disease with no chemotherapeutic agents approved by the FDA for its treatment. AA has a unique biology in which it frequently forms diffuse peritoneal metastases but almost never spreads via a hematogenous route and rarely spreads to lymphatics. Given the localization of AA to the peritoneal space, intraperitoneal (IP) delivery of chemotherapy could be an effective treatment strategy. Here, we tested the efficacy …

Abemaciclib Is Effective In Palbociclib-Resistant Hormone Receptor-Positive Metastatic Breast Cancers, Juliana Navarro-Yepes, Nicole M Kettner, Xiayu Rao, Cassandra Santaella Bishop, Tuyen N Bui, Hannah F Wingate, Akshara Singareeka Raghavendra, Yan Wang, Jing Wang, Aysegul A Sahin, Funda Meric-Bernstam, Kelly K Hunt, Senthil Damodaran, Debu Tripathy, Khandan Keyomarsi

Faculty, Staff and Student Publications

Cyclin-dependent kinases 4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) is standard of care for patients with hormone receptor (HR)-positive, HER2-negative metastatic breast cancer (MBC). However, resistance to CDK4/6is plus ET remains a clinical problem with limited therapeutic options following disease progression. Different CDK4/6is might have distinct mechanisms of resistance, and therefore using them sequentially or targeting their differentially altered pathways could delay disease progression. To understand pathways leading to resistance to the CDK4/6is palbociclib and abemaciclib, we generated multiple in vitro models of palbociclib-resistant (PR) and abemaciclib-resistant (AR) cell lines as well as in vivo patient-derived xenografts (PDX) and ex …

Endocrine Therapy Synergizes With Smac Mimetics To Potentiate Antigen Presentation And Tumor Regression In Hormone Receptor-Positive Breast Cancer, Francisco Hermida-Prado, Yingtian Xie, Shira Sherman, Zsuzsanna Nagy, Douglas Russo, Tara Akhshi, Zhengtao Chu, Avery Feit, Marco Campisi, Minyue Chen, Agostina Nardone, Cristina Guarducci, Klothilda Lim, Alba Font-Tello, Irene Lee, Juana García-Pedrero, Israel Cañadas, Judith Agudo, Ying Huang, Tal Sella, Qingchun Jin, Nabihah Tayob, Elizabeth A Mittendorf, Sara M Tolaney, Xintao Qiu, Henry Long, William F Symmans, Jia-Ren Lin, Sandro Santagata, Isabelle Bedrosian, Denise A Yardley, Ingrid A Mayer, Edward T Richardson, Giacomo Oliveira, Catherine J Wu, Eugene F Schuster, Mitch Dowsett, Alana L Welm, David Barbie, Otto Metzger, Rinath Jeselsohn

Faculty, Staff and Student Publications

Immunotherapies have yet to demonstrate significant efficacy in the treatment of hormone receptor-positive (HR+) breast cancer. Given that endocrine therapy (ET) is the primary approach for treating HR+ breast cancer, we investigated the effects of ET on the tumor immune microenvironment (TME) in HR+ breast cancer. Spatial proteomics of primary HR+ breast cancer samples obtained at baseline and after ET from patients enrolled in a neoadjuvant clinical trial (NCT02764541) indicated that ET upregulated β2-microglobulin and influenced the TME in a manner that promotes enhanced immunogenicity. To gain a deeper understanding of the underlying mechanisms, the intrinsic effects of …

Setd2 Loss And Atr Inhibition Synergize To Promote Cgas Signaling And Immunotherapy Response In Renal Cell Carcinoma, Xian-De Liu, Yan-Ting Zhang, Daniel J Mcgrail, Xuesong Zhang, Truong Lam, Anh Hoang, Elshad Hasanov, Ganiraju Manyam, Christine B Peterson, Haifeng Zhu, Shwetha V Kumar, Rehan Akbani, Patrick G Pilie, Nizar M Tannir, Guang Peng, Eric Jonasch

Faculty, Staff and Student Publications

PURPOSE: Immune checkpoint blockade (ICB) demonstrates durable clinical benefits in a minority of patients with renal cell carcinoma (RCC). We aimed to identify the molecular features that determine the response and develop approaches to enhance it.

EXPERIMENTAL DESIGN: We investigated the effects of SET domain-containing protein 2 (SETD2) loss on the DNA damage response pathway, the cytosolic DNA-sensing pathway, the tumor immune microenvironment, and the response to ataxia telangiectasia and rad3-related (ATR) and checkpoint inhibition in RCC.

RESULTS: ATR inhibition activated the cyclic GMP-AMP synthase (cGAS)-interferon regulatory factor 3 (IRF3)-dependent cytosolic DNA-sensing pathway, resulting in the concurrent expression of inflammatory …

Chronic Kidney Disease Promotes Atrial Fibrillation Via Inflammasome Pathway Activation, Jia Song, Jose Alberto Navarro-Garcia, Jiao Wu, Arnela Saljic, Issam Abu-Taha, Luge Li, Satadru K Lahiri, Joshua A Keefe, Yuriana Aguilar-Sanchez, Oliver M Moore, Yue Yuan, Xiaolei Wang, Markus Kamler, William E Mitch, Gema Ruiz-Hurtado, Zhaoyong Hu, Sandhya S Thomas, Dobromir Dobrev, Xander Ht Wehrens, Na Li

Faculty, Staff and Students Publications

Chronic kidney disease (CKD) is associated with a higher risk of atrial fibrillation (AF). The mechanistic link between CKD and AF remains elusive. IL-1β, a main effector of NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation, is a key modulator of conditions associated with inflammation, such as AF and CKD. Circulating IL-1β levels were elevated in patients with CKD who had AF (versus patients with CKD in sinus rhythm). Moreover, NLRP3 activity was enhanced in atria of patients with CKD. To elucidate the role of NLRP3/IL-1β signaling in the pathogenesis of CKD-induced AF, Nlrp3-/- and WT mice were subjected to …

Kinome Reprogramming Is A Targetable Vulnerability In Esr1 Fusion-Driven Breast Cancer, Xuxu Gou, Beom-Jun Kim, Meenakshi Anurag, Jonathan T Lei, Meggie N Young, Matthew V Holt, Diana Fandino, Craig T Vollert, Purba Singh, Mohammad A Alzubi, Anna Malovannaya, Lacey E Dobrolecki, Michael T Lewis, Shunqiang Li, Charles E Foulds, Matthew J Ellis

Faculty, Staff and Students Publications

Transcriptionally active ESR1 fusions (ESR1-TAF) are a potent cause of breast cancer endocrine therapy (ET) resistance. ESR1-TAFs are not directly druggable because the C-terminal estrogen/anti-estrogen-binding domain is replaced with translocated in-frame partner gene sequences that confer constitutive transactivation. To discover alternative treatments, a mass spectrometry (MS)-based kinase inhibitor pulldown assay (KIPA) was deployed to identify druggable kinases that are upregulated by diverse ESR1-TAFs. Subsequent explorations of drug sensitivity validated RET kinase as a common therapeutic vulnerability despite remarkable ESR1-TAF C-terminal sequence and structural diversity. Organoids and xenografts from a pan-ET-resistant patient-derived xenograft model that harbors the ESR1-e6>YAP1 TAF were …

Specialized Astrocytes Mediate Glutamatergic Gliotransmission In The Cns, Roberta De Ceglia, Ada Ledonne, David Gregory Litvin, Barbara Lykke Lind, Giovanni Carriero, Emanuele Claudio Latagliata, Erika Bindocci, Maria Amalia Di Castro, Iaroslav Savtchouk, Ilaria Vitali, Anurag Ranjak, Mauro Congiu, Tara Canonica, William Wisden, Kenneth Harris, Manuel Mameli, Nicola Mercuri, Ludovic Telley, Andrea Volterra

Biomedical Sciences Faculty Research and Publications

Multimodal astrocyte–neuron communications govern brain circuitry assembly and function. For example, through rapid glutamate release, astrocytes can control excitability, plasticity and synchronous activity of synaptic networks, while also contributing to their dysregulation in neuropsychiatric conditions. For astrocytes to communicate through fast focal glutamate release, they should possess an apparatus for Ca2+-dependent exocytosis similar to neurons. However, the existence of this mechanism has been questioned owing to inconsistent data and a lack of direct supporting evidence. Here we revisited the astrocyte glutamate exocytosis hypothesis by considering the emerging molecular heterogeneity of astrocytes and using molecular, bioinformatic and imaging approaches, together with …

Novel Strategies In Antithrombotic Therapy: Targeting Thrombosis While Preserving Hemostasis, Martha M. S. Sim, Semekidus Shiferawe, Jeremy P. Wood

Saha Cardiovascular Research Center Faculty Publications

Antithrombotic therapy is a delicate balance between the benefits of preventing a thrombotic event and the risks of inducing a major bleed. Traditional approaches have included antiplatelet and anticoagulant medications, require careful dosing and monitoring, and all carry some risk of bleeding. In recent years, several new targets have been identified, both in the platelet and coagulation systems, which may mitigate this bleeding risk. In this review, we briefly describe the current state of antithrombotic therapy, and then present a detailed discussion of the new generation of drugs that are being developed to target more safely existing or newly identified …

Co-Targeting Bcl-Xl And Bcl-2 By Protac 753b Eliminates Leukemia Cells And Enhances Efficacy Of Chemotherapy By Targeting Senescent Cells, Yannan Jia, Lina Han, Cassandra L Ramage, Zhe Wang, Connie C Weng, Lei Yang, Simona Colla, Helen Ma, Weiguo Zhang, Michael Andreeff, Naval Daver, Nitin Jain, Naveen Pemmaraju, Kapil Bhalla, Satu Mustjoki, Peiyi Zhang, Guangrong Zheng, Daohong Zhou, Qi Zhang, Marina Konopleva

Faculty, Staff and Student Publications

BCL-XL and BCL-2 are key anti-apoptotic proteins and validated cancer targets. 753B is a novel BCL-XL/BCL-2 proteolysis targeting chimera (PROTAC) that targets both BCL-XL and BCL-2 to the von Hippel-Lindau (VHL) E3 ligase, leading to BCLX L/BCL-2 ubiquitination and degradation selectively in cells expressing VHL. Because platelets lack VHL expression, 753B spares on-target platelet toxicity caused by the first-generation dual BCL-XL/BCL-2 inhibitor navitoclax (ABT-263). Here, we report pre-clinical single-agent activity of 753B against different leukemia subsets. 753B effectively reduced cell viability and induced dose-dependent degradation of BCL-XL and BCL-2 in a subset of hematopoietic cell lines, acute myeloid leukemia (AML) …

Zyxin Inhibits The Epithelial-Mesenchymal Transition Process In Gastric Cancer By Upregulating Sirt1, Jing Lou, Sha Geng, Wei He, Song-Bai Liu, Xinghong Shi, Ying Chang, Shiyuan Han, Panting Qian, Hesham M Amin, Yao-Hua Song, Yangxin Li, Jin Zhou

Faculty, Staff and Student Publications

Tumor development relies on the stemness of cancer stem cells, which is regulated by environmental cues. Previous studies have shown that zyxin can inhibit the expression of genes for embryonic stem cell status. In the present study, the expression levels of zyxin protein in cancer tissues and adjacent noncancerous tissues from 73 gastric cancer patients with different clinical stages were analyzed by Western blot. We showed that the relative expression levels of zyxin in gastric cancer tissues (cancer tissues/adjacent tissues) were significantly downregulated in advanced clinical stages. Overexpression of zyxin inhibited the stemness and epithelial-mesenchymal transition (EMT) processes in gastric …

Therapeutic Effects Of Combining Curcumin And Swimming In Osteoarthritis Using A Rat Model, Mona M Saber, Manal Moustafa Mahmoud, Hesham M Amin, Reham M Essam

Faculty, Staff and Student Publications

Osteoarthritis (OA) is a common debilitating degenerative disease of the elderly. We aimed to study the therapeutic effects of combining curcumin and swimming in monosodium iodoacetate (MIA)-induced OA in a rat model. The rats were divided into 5 groups (n = 9). Group 1 received saline and served as a control group. Groups 2-5 were injected intra-articularly in the right knee with 100 μL MIA. One week later, groups 3 and 5 were started on daily swimming sessions that gradually increased to 20-mins per session, and for groups 4 and 5, oral curcumin was administered at a dose of 200 …

Young-Onset Rectal Cancer: Unique Tumoral Microbiome And Correlation With Response To Neoadjuvant Therapy, Michael G White, Ashish Damania, Jumanah Alshenaifi, Pranoti Sahasrabhojane, Oliver Peacock, Jillian Losh, Matthew C Wong, Zuzana Lutter-Berkova, George J Chang, Andrew Futreal, Jennifer A Wargo, Nadim J Ajami, Scott Kopetz, Y Nancy You

Faculty, Staff and Student Publications

OBJECTIVE: External exposures, the host, and the microbiome interact in oncology. We aimed to investigate tumoral microbiomes in young-onset rectal cancers (YORCs) for profiles potentially correlative with disease etiology and biology.

BACKGROUND: YORC is rapidly increasing, with 1 in 4 new rectal cancer cases occurring under the age of 50 years. Its etiology is unknown.

METHODS: YORC (old) or later-onset rectal cancer (LORC, ≥50 y old) patients underwent pretreatment biopsied of tumor and tumor-adjacent normal (TAN) tissue. After whole genome sequencing, metagenomic analysis quantified microbial communities comparing tumors versus TANs and YORCs versus LORCs, controlling for multiple testing. Response to …

Emphasizing Others’ Persistence Can Promote Unwarranted Social Inferences In Children And Adults, Jamie Amemiya, Gail D Heyman, Caren M Walker

Faculty, Staff and Student Publications

People often hear stories about individuals who persist to overcome their constraints. While these stories can be motivating, emphasizing others’ persistence may promote unwarranted judgments about constrained individuals who do not persist. Using a developmental social inference task (Study 1a: n = 124 U.S. children, 5 to 12 years of age; Study 1b [n = 135] and Study 2 [n = 120]: U.S. adults), the present research tested whether persistence stories lead people to infer that a constrained individual who does not persist, and instead accepts the lower-quality option that is available to them, prefers it over a …

A Machine Learning Approach That Measures Ph Using Acidocest Mri Of Iopamidol, Tianzhe Li, Julio Cárdenas-Rodríguez, Priya N Trakru, Mark D Pagel

Faculty, Staff and Student Publications

Tumor acidosis is an important biomarker for aggressive tumors, and extracellular pH (pHe) of the tumor microenvironment can be used to predict and evaluate tumor responses to chemotherapy and immunotherapy. AcidoCEST MRI measures tumor pHe by exploiting the pH-dependent chemical exchange saturation transfer (CEST) effect of iopamidol, an exogenous CT agent repurposed for CEST MRI. However, all pH fitting methodologies for acidoCEST MRI data have limitations. Herein we present results of the application of machine learning for extracting pH values from CEST Z-spectra of iopamidol. We acquired 36,000 experimental CEST spectra from 200 phantoms of iopamidol prepared at five concentrations, …

Innately Expressed Estrogen-Related Receptors In The Skeletal Muscle Are Indispensable For Exercise Fitness, Ashok Kumar, Vihang A Narkar

Faculty, Staff and Student Publications

Peripheral arterial disease (PAD) is a prevalent cardiovascular complication of limb vascular insufficiency, causing ischemic injury, mitochondrial metabolic damage and functional impairment in the skeletal muscle, and ultimately leading to immobility and mortality. While potential therapies have been mostly focussed on revascularization, none of the currently available pharmacological treatments are fully effective in PAD, often leading to amputations, particularly in chronic metabolic diseases. One major limitation of focussed angiogenesis and revascularization as a therapeutic strategy is a limited effect on metabolic restoration and muscle regeneration in the affected limb. Therefore, additional preclinical investigations are needed to discover novel treatment options …

Elongation Of Very Long Chain Fatty Acids-3 (Elovl3) Is Activated By Zhx2 And Is A Regulator Of Cell Cycle Progression, Kate Townsend Creasy, Hui Ren, Jieyun Jiang, Martha L. Peterson, Brett T. Spear

Markey Cancer Center Faculty Publications

Zinc fingers and homeoboxes 2 (Zhx2) are transcriptional regulators of liver gene expression with key functions in embryonic development as well as tissue regeneration in response to damage and disease, presumably through its control of target genes. Previous microarray data suggested that elongation of very long chain fatty acids-3 (Elovl3), a member of the ELOVL family of enzymes that synthesize very long chain fatty acids (VLCFAs), is a putative Zhx2 target gene. VLCFAs are core component of ceramides and other bioactive sphingolipids that are often dysregulated in diseases and regulate key cellular processes including proliferation. Since several previously identified Zhx2 …