Digital Commons Network^™

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 …

Phenotype And Fate Of Liver-Resident Cd8 T Cells During Acute And Chronic Hepacivirus Infection, Piyush Dravid, Satyapramod Murthy, Zayed Attia, Cole Cassady, Rahul Chandra, Sheetal Trivedi, Ashish Vyas, John Gridley, Brantley Holland, Anuradha Kumari, Arash Grakoui, John M Cullen, Christopher M Walker, Himanshu Sharma, Amit Kapoor

Faculty, Staff and Student Publications

Immune correlates of hepatitis C virus (HCV) clearance and control remain poorly defined due to the lack of an informative animal model. We recently described acute and chronic rodent HCV-like virus (RHV) infections in lab mice. Here, we developed MHC class I and class II tetramers to characterize the serial changes in RHV-specific CD8 and CD4 T cells during acute and chronic infection in C57BL/6J mice. RHV infection induced rapid expansion of T cells targeting viral structural and nonstructural proteins. After virus clearance, the virus-specific T cells transitioned from effectors to long-lived liver-resident memory T cells (TRM). The effector and …

An Efficient Strategy For Evaluating New Non-Invasive Screening Tests For Colorectal Cancer: The Guiding Principles, Robert S Bresalier, Carlo Senore, Graeme P Young, James Allison, Robert Benamouzig, Sally Benton, Patrick M M Bossuyt, Luis Caro, Beatriz Carvalho, Han-Mo Chiu, Veerle M H Coupé, Willemijn De Klaver, Clasine Maria De Klerk, Evelien Dekker, Sunil Dolwani, Callum G Fraser, William Grady, Lydia Guittet, Samir Gupta, Stephen P Halloran, Ulrike Haug, Geir Hoff, Steven Itzkowitz, Tim Kortlever, Anastasios Koulaouzidis, Uri Ladabaum, Beatrice Lauby-Secretan, Mārcis Leja, Bernard Levin, Theodore Robert Levin, Finlay Macrae, Gerrit A Meijer, Joshua Melson, Colm O'Morain, Susan Parry, Linda Rabeneck, David F Ransohoff, Roque Sáenz, Hiroshi Saito, Silvia Sanduleanu-Dascalescu, Robert E Schoen, Kevin Selby, Harminder Singh, Robert J C Steele, Joseph J Y Sung, Erin Leigh Symonds, Sidney J Winawer, Members Of The World Endoscopy Colorectal Cancer Screening New Test Evaluation Expert Working Group

Faculty, Staff and Student Publications

OBJECTIVE: New screening tests for colorectal cancer (CRC) are rapidly emerging. Conducting trials with mortality reduction as the end point supporting their adoption is challenging. We re-examined the principles underlying evaluation of new non-invasive tests in view of technological developments and identification of new biomarkers.

DESIGN: A formal consensus approach involving a multidisciplinary expert panel revised eight previously established principles.

RESULTS: Twelve newly stated principles emerged. Effectiveness of a new test can be evaluated by comparison with a proven comparator non-invasive test. The faecal immunochemical test is now considered the appropriate comparator, while colonoscopy remains the diagnostic standard. For a …

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 …

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) …

Combining Clinical And Biological Data To Predict Progressive Pulmonary Fibrosis In Patients With Systemic Sclerosis Despite Immunomodulatory Therapy, Elizabeth R Volkmann, Holly Wilhalme, Shervin Assassi, Grace Hyun J Kim, Jonathan Goldin, Masataka Kuwana, Donald P Tashkin, Michael D Roth

Faculty, Staff and Student Publications

OBJECTIVE: Progressive pulmonary fibrosis (PPF) is the leading cause of death in systemic sclerosis (SSc). This study aimed to develop a clinical prediction nomogram using clinical and biological data to assess risk of PPF among patients receiving treatment of SSc-related interstitial lung disease (SSc-ILD).

METHODS: Patients with SSc-ILD who participated in the Scleroderma Lung Study II (SLS II) were randomized to treatment with either mycophenolate mofetil (MMF) or cyclophosphamide (CYC). Clinical and biological parameters were analyzed using univariable and multivariable logistic regression, and a nomogram was created to assess the risk of PPF and validated by bootstrap resampling.

RESULTS: Among …

Existing Evidence For Influenza B Virus Adaptations To Drive Replication In Humans As The Primary Host, Matthew J. Pekarek, Eric A. Weaver

Nebraska Center for Virology: Faculty Publications

Influenza B virus (IBV) is one of the two major types of influenza viruses that circulate each year. Unlike influenza A viruses, IBV does not harbor pandemic potential due to its lack of historical circulation in non-human hosts. Many studies and reviews have highlighted important factors for host determination of influenza A viruses. However, much less is known about the factors driving IBV replication in humans. We hypothesize that similar factors influence the host restriction of IBV. Here, we compile and review the current understanding of host factors crucial for the various stages of the IBV viral replication cycle. While …

Severe Covid-19 Outcomes And Hematological Cancers: The Clot Thickens-Are Platelets The Culprit?, Lenard M Lichtenberger, K Vinod Vijayan

Faculty, Staff and Student Publications

No abstract provided.

Updates On The Immune Cell Basis Of Hepatic Ischemia-Reperfusion Injury, Mi Jeong Heo, Ji Ho Suh, Kyle L Poulsen, Cynthia Ju, Kang Ho Kim

Faculty, Staff and Student Publications

Liver ischemia-reperfusion injury (IRI) is the main cause of organ dysfunction and failure after liver surgeries including organ transplantation. The mechanism of liver IRI is complex and numerous signals are involved but cellular metabolic disturbances, oxidative stress, and inflammation are considered the major contributors to liver IRI. In addition, the activation of inflammatory signals exacerbates liver IRI by recruiting macrophages, dendritic cells, and neutrophils, and activating NK cells, NKT cells, and cytotoxic T cells. Technological advances enable us to understand the role of specific immune cells during liver IRI. Accordingly, therapeutic strategies to prevent or treat liver IRI have been …

Purification And Characterization Of Mitochondrial Mg2+-Independent Sphingomyelinase From Rat Brain, Jong Min Choi, Yongwei Piao, Kyong Hoon Ahn, Seok Kyun Kim, Jong Hoon Won, Jae Hong Lee, Ji Min Jang, In Chul Shin, Zhicheng Fu, Sung Yun Jung, Eui Man Jeong, Dae Kyong Kim

Faculty, Staff and Students Publications

Sphingomyelinase (SMase) catalyzes ceramide production from sphingomyelin. Ceramides are critical in cellular responses such as apoptosis. They enhance mitochondrial outer membrane permeabilization (MOMP) through self-assembly in the mitochondrial outer membrane to form channels that release cytochrome c from intermembrane space (IMS) into the cytosol, triggering caspase-9 activation. However, the SMase involved in MOMP is yet to be identified. Here, we identified a mitochondrial Mg

A Ck2 And Sumo-Dependent, Pml Nb-Involved Regulatory Mechanism Controlling Blm Ubiquitination And G-Quadruplex Resolution, Shichang Liu, Erin Atkinson, Adriana Paulucci-Holthauzen, Bin Wang

Faculty, Staff and Student Publications

The Boom syndrome helicase (BLM) unwinds a variety of DNA structures such as Guanine (G)-quadruplex. Here we reveal a role of RNF111/Arkadia and its paralog ARKL1, as well as Promyelocytic Leukemia Nuclear Bodies (PML NBs), in the regulation of ubiquitination and control of BLM protein levels. RNF111 exhibits a non-canonical SUMO targeted E3 ligase (STUBL) activity targeting BLM ubiquitination in PML NBs. ARKL1 promotes RNF111 localization to PML NBs through SUMO-interacting motif (SIM) interaction with SUMOylated RNF111, which is regulated by casein kinase 2 (CK2) phosphorylation of ARKL1 at a serine residue near the ARKL1 SIM domain. Upregulated BLM in …

The Role Of Zinc In Psd-95 Palmitoyl Modification, Luis F. Acosta, Lili Guerra, Safiya Syed, Ivonn Ruvalcaba, Yonghong Zhang, Xiaoqian Fang

Research Symposium

Postsynaptic density-95 (PSD-95) is a membrane-associated guanylate kinase that mediates localization of receptors in the excitatory postsynaptic density. It has been reported that PSD-95 mediates postsynaptic localization of NMDA receptors and anchors postsynaptic AMPAR receptors mainly through its postsynaptic membrane targeting by its N-terminal palmitoylation. Recent studies have shown that Ca2+/calmodulin blocks palmitoylation of PSD-95 by binding at the N-terminus of PSD-95, which promotes dissociation of PSD-95 from the postsynaptic membrane and causes loss of surface AMPARs in cultured neurons. Another metal ion zinc is found in various areas of the brain. As an endogenous neuromodulator, zinc plays a role …

Natural Remedies To Combat Aberrant Hallmark Signatures Including Altered Glycosylation In Oral Carcinoma, Kruti A. Mehta, Jayendra B. Patel, Prabhudas S. Patel

Research Symposium

Background: Tobacco associated oral cancers remain a major concern in India with higher incidence and mortality making it an Indian-centric burning issue. To combat this dreadful disease, we investigated effects of certain natural compounds on the hallmark signatures including glycosylation transcripts levels in oral carcinoma.

Methods: The tongue carcinoma cells- SAS cells were treated with tobacco compounds, natural compounds and Cisplatin. RNA was isolated from the cells and converted to cDNA. RT-qPCR was performed to evaluate expression levels of various genes.

Results: The treatment of tobacco compounds resulted in similar pattern of altered makers (ST3GAL1, NEU3, FUT5, FUT6, MMP2, BCL2) …

Adaptive Octree Meshes For Simulation Of Extracellular Electrophysiology, Christopher Bc Girard, Dong Song

Engineering Faculty Articles and Research

Objective. The interaction between neural tissues and artificial electrodes is crucial for understanding and advancing neuroscientific research and therapeutic applications. However, accurately modeling this space around the neurons rapidly increases the computational complexity of neural simulations. Approach. This study demonstrates a dynamically adaptive simulation method that greatly accelerates computation by adjusting spatial resolution of the simulation as needed. Use of an octree structure for the mesh, in combination with the admittance method for discretizing conductivity, provides both accurate approximation and ease of modification on-the-fly. Main results. In tests of both local field potential estimation and multi-electrode stimulation, dynamically adapted meshes …

Pediatric Hepatocellular Adenomas: What Is Known And What Is New?, Andres F Espinoza, Sanjeev A Vasudevan, Prakash M Masand, Dolores H Lòpez-Terrada, Kalyani R Patel

Faculty, Staff and Students Publications

Current understanding and classification of pediatric hepatocellular adenomas (HCA) are largely based on adult data. HCAs are rare in children and, unlike in adults, are often seen in the context of syndromes or abnormal background liver. Attempts to apply the adult classification to pediatric tumors have led to several "unclassifiable" lesions. Although typically considered benign, few can show atypical features and those with beta-catenin mutations have a risk for malignant transformation. Small lesions can be monitored while larger (>5.0 cm) lesions are excised due to symptoms or risk of bleeding/rupture, etc. Management depends on gender, age, underlying liver disease, …

Vadadustat For Treatment Of Anemia In Patients With Dialysis-Dependent Chronic Kidney Disease Receiving Peritoneal Dialysis, Mark J Sarnak, Rajiv Agarwal, Neil Boudville, Pradip C P Chowdhury, Kai-Uwe Eckardt, Carlos R Gonzalez, Laura A Kooienga, Mark J Koury, Kwabena A Ntoso, Wenli Luo, Patrick S Parfrey, Dennis L Vargo, Wolfgang C Winkelmayer, Zhiqun Zhang, Glenn M Chertow

Faculty, Staff and Students Publications

BACKGROUND: Hypoxia-inducible factor prolyl hydroxylase inhibitors such as vadadustat may provide an oral alternative to injectable erythropoiesis-stimulating agents for treating anemia in patients receiving peritoneal dialysis. In two randomized (1:1), global, phase 3, open-label, sponsor-blind, parallel-group, active-controlled noninferiority trials in patients with dialysis-dependent chronic kidney disease (INNO2VATE), vadadustat was noninferior to darbepoetin alfa with respect to cardiovascular safety and hematological efficacy. Vadadustat's effects in patients receiving only peritoneal dialysis is unclear.

METHODS: We conducted a post hoc analysis of patients in the INNO2VATE trials receiving peritoneal dialysis at baseline. The prespecified primary safety endpoint was time to first major cardiovascular …

New Jak3-Insl3 Fusion Transcript-An Oncogenic Event In Cutaneous T-Cell Lymphoma, Loka Reddy Velatooru, Cheng Hui Hu, Pedram Bijani, Xiaohong Wang, Pierr Bojaxhi, Hao Chen, Madeleine Duvic, Xiao Ni

Faculty, Staff and Student Publications

Constitutively activated tyrosine kinase JAK3 is implicated in the pathogenesis of cutaneous T-cell lymphomas (CTCL). The mechanisms of constitutive JAK3 activation are unknown although a JAK3 mutation was reported in a small portion of CTCL patients. In this study, we assessed the oncogenic roles of a newly identified JAK3-INSL3 fusion transcript in CTCL. Total RNA from malignant T-cells in 33 patients with Sézary syndrome (SS), a leukemic form of CTCL, was examined for the new JAK3-INSL3 fusion transcript by RT-PCR followed by Sanger sequencing. The expression levels were assessed by qPCR and correlated with patient survivals. Knockdown and/or knockout assays …

Heterogenous Lung Inflammation Ct Patterns Distinguish Pneumonia And Immune Checkpoint Inhibitor Pneumonitis And Complement Blood Biomarkers In Acute Myeloid Leukemia: Proof Of Concept, Muhammad Aminu, Naval Daver, Myrna C B Godoy, Girish Shroff, Carol Wu, Luis F Torre-Sada, Alberto Goizueta, Vickie R Shannon, Saadia A Faiz, Mehmet Altan, Guillermo Garcia-Manero, Hagop Kantarjian, Farhad Ravandi-Kashani, Tapan Kadia, Marina Konopleva, Courtney Dinardo, Sherry Pierce, Aung Naing, Sang T Kim, Dimitrios P Kontoyiannis, Fareed Khawaja, Caroline Chung, Jia Wu, Ajay Sheshadri

Faculty, Staff and Student Publications

BACKGROUND: Immune checkpoint inhibitors (ICI) may cause pneumonitis, resulting in potentially fatal lung inflammation. However, distinguishing pneumonitis from pneumonia is time-consuming and challenging. To fill this gap, we build an image-based tool, and further evaluate it clinically alongside relevant blood biomarkers.

MATERIALS AND METHODS: We studied CT images from 97 patients with pneumonia and 29 patients with pneumonitis from acute myeloid leukemia treated with ICIs. We developed a CT-derived signature using a habitat imaging algorithm, whereby infected lungs are segregated into clusters ("habitats"). We validated the model and compared it with a clinical-blood model to determine whether imaging can add …

Palmitoylation As A Regulator Of Maguk Proteins Postsynaptic Localization, Rozena Shirvani-Arani, Santiago Balderas, Yonghong Zhang, Xioaqian Fang

Research Symposium

Synaptic plasticity is the ability of the brain to make changes and the changes occur at synapses. To achieve the complicated functions, a good number of proteins are present at synapse and are called synaptic proteins. To stabilize these proteins at synapses, proteins are modified through posttranslational modifications (PTMs). The most studied PTMs include phosphorylation, acetylation, ubiquitination, glycosylation, palmitoylation, etc. Palmitoylation is a type of lipid modification and has received more attention recently for its contribution to protein trafficking, localization, and interaction in various synaptic plasticity. The membrane-associated guanylate kinase (MAGUK) family includes PSD-95, PSD-93 (also known as chapsyn-110), SAP102, …

Cabozantinib And Il-27 Combinatorial Therapy For Bone-Metastatic Prostate Cancer, Shreya Kumar, Grace E. Mulia, Marxa L. Figueiredo

Purdue University Libraries Open Access Publishing Fund

Introduction: Prostate cancer is the second leading cause of cancer-related death among American men. Prostate tumor cells exhibit significant tropism for the bone and once metastasis occurs, survival rates fall significantly. Current treatment options are not curative and focus on symptom management. Immunotherapies are rapidly emerging as a possible therapeutic option for a variety of cancers including prostate cancer, however, variable patient response remains a concern. Chemotherapies, like cabozantinib, can have immune-priming effects which sensitize tumors to immunotherapies. Additionally, lower doses of chemotherapy can be used in this context which can reduce patient side effects. We hypothesized that a combination …

Regulation Of Syntaxin3b-Mediated Membrane Fusion By T14, Munc18, And Complexin, Rajkishor Nishad, Miguel Betancourt-Solis, Himani Dey, Ruth Heidelberger, James A Mcnew

Faculty, Staff and Student Publications

Retinal neurons that form ribbon-style synapses operate over a wide dynamic range, continuously relaying visual information to their downstream targets. The remarkable signaling abilities of these neurons are supported by specialized presynaptic machinery, one component of which is syntaxin3B. Syntaxin3B is an essential t-SNARE protein of photoreceptors and bipolar cells that is required for neurotransmitter release. It has a light-regulated phosphorylation site in its N-terminal domain at T14 that has been proposed to modulate membrane fusion. However, a direct test of the latter has been lacking. Using a well-controlled in vitro fusion assay, we found that a phosphomimetic T14 syntaxin3B …

Lack Of Methylation Changes In Gjb2 And Rb1 Non-Coding Regions Of Cochlear Implant Patients With Sensorineural Hearing Loss, Angelo Augusto M Sumalde, Ivana V Yang, Talitha Karisse L Yarza, Celina Ann M Tobias-Grasso, Ma Leah C Tantoco, Elizabeth Davidson, Abner L Chan, Mahshid S Azamian, Teresa Luisa G Cruz, Seema R Lalani, Maria Rina T Reyes-Quintos, Eva Maria Cutiongco-De La Paz, Regie Lyn P Santos-Cortez, Charlotte M Chiong

Faculty, Staff and Students Publications

OBJECTIVE: Recent advances in epigenetic studies continue to reveal novel mechanisms of gene regulation and control, however little is known on the role of epigenetics in sensorineural hearing loss (SNHL) in humans. We aimed to investigate the methylation patterns of two regions, one in

METHODS: We investigated an RB1 promoter region that was previously identified as differentially methylated in children with SNHL and lead exposure. Additionally, we investigated a sequence in an enhancer-like region within GJB2 that contains four CpGs in close proximity. Bisulfite conversion was performed on salivary DNA samples from 15 children with SNHL and 45 unrelated ethnically-matched …

Insulin Resistance And Insulin Handling In Chronic Kidney Disease, Vishnu P Parvathareddy, Jiao Wu, Sandhya S Thomas

Faculty, Staff and Students Publications

Insulin regulates energy metabolism involving multiple organ systems. Insulin resistance (IR) occurs when organs exhibit reduced insulin sensitivity, leading to difficulties in maintaining glucose homeostasis. IR ensures decades prior to development of overt diabetes and can cause silent metabolic derangements. IR is typically seen very early in the course of chronic kidney disease (CKD) and is evident even when the estimated glomerular filtration rate (eGFR) is within the normal range and IR persists at various stages of kidney disease. In this article, we will discuss insulin handling by the kidneys, mechanisms responsible for IR in CKD, measurements and management of …

Integrated Molecular And Multiparametric Mri Mapping Of High-Grade Glioma Identifies Regional Biologic Signatures, Leland S Hu, Fulvio D'Angelo, Taylor M Weiskittel, Francesca P Caruso, Shannon P Fortin Ensign, Mylan R Blomquist, Matthew J Flick, Lujia Wang, Christopher P Sereduk, Kevin Meng-Lin, Gustavo De Leon, Ashley Nespodzany, Javier C Urcuyo, Ashlyn C Gonzales, Lee Curtin, Erika M Lewis, Kyle W Singleton, Timothy Dondlinger, Aliya Anil, Natenael B Semmineh, Teresa Noviello, Reyna A Patel, Panwen Wang, Junwen Wang, Jennifer M Eschbacher, Andrea Hawkins-Daarud, Pamela R Jackson, Itamar S Grunfeld, Christian Elrod, Gina L Mazza, Sam C Mcgee, Lisa Paulson, Kamala Clark-Swanson, Yvette Lassiter-Morris, Kris A Smith, Peter Nakaji, Bernard R Bendok, Richard S Zimmerman, Chandan Krishna, Devi P Patra, Naresh P Patel, Mark Lyons, Matthew Neal, Kliment Donev, Maciej M Mrugala, Alyx B Porter, Scott C Beeman, Todd R Jensen, Kathleen M Schmainda, Yuxiang Zhou, Leslie C Baxter, Christopher L Plaisier, Jing Li, Hu Li, Anna Lasorella, C Chad Quarles, Kristin R Swanson, Michele Ceccarelli, Antonio Iavarone, Nhan L Tran

Faculty, Staff and Student Publications

Sampling restrictions have hindered the comprehensive study of invasive non-enhancing (NE) high-grade glioma (HGG) cell populations driving tumor progression. Here, we present an integrated multi-omic analysis of spatially matched molecular and multi-parametric magnetic resonance imaging (MRI) profiling across 313 multi-regional tumor biopsies, including 111 from the NE, across 68 HGG patients. Whole exome and RNA sequencing uncover unique genomic alterations to unresectable invasive NE tumor, including subclonal events, which inform genomic models predictive of geographic evolution. Infiltrative NE tumor is alternatively enriched with tumor cells exhibiting neuronal or glycolytic/plurimetabolic cellular states, two principal transcriptomic pathway-based glioma subtypes, which respectively demonstrate …

Targeting Eif4a Triggers An Interferon Response To Synergize With Chemotherapy And Suppress Triple-Negative Breast Cancer, Na Zhao, Elena B Kabotyanski, Alexander B Saltzman, Anna Malovannaya, Xueying Yuan, Lucas C Reineke, Nadia Lieu, Yang Gao, Diego A Pedroza, Sebastian J Calderon, Alex J Smith, Clark Hamor, Kazem Safari, Sara Savage, Bing Zhang, Jianling Zhou, Luisa M Solis, Susan G Hilsenbeck, Cheng Fan, Charles M Perou, Jeffrey M Rosen

Faculty, Staff and Students Publications

Protein synthesis is frequently dysregulated in cancer and selective inhibition of mRNA translation represents an attractive cancer therapy. Here, we show that therapeutically targeting the RNA helicase eIF4A by Zotatifin, the first-in-class eIF4A inhibitor, exerts pleiotropic effects on both tumor cells and the tumor immune microenvironment in a diverse cohort of syngeneic triple-negative breast cancer (TNBC) mouse models. Zotatifin not only suppresses tumor cell proliferation but also directly repolarizes macrophages towards an M1-like phenotype and inhibits neutrophil infiltration, which sensitizes tumors to immune checkpoint blockade. Mechanistic studies revealed that Zotatifin reprograms the tumor translational landscape, inhibits the translation of Sox …

Development Of A Xylose-Inducible Promoter And Riboswitch Combination System For Manipulating Gene Expression In Fusobacterium Nucleatum, Bibek G C, Peng Zhou, Arindam Naha, Jianhua Gu, Chenggang Wu

Faculty, Staff and Student Publications

Inducible gene expression systems are important for studying bacterial gene function, yet most exhibit leakage. In this study, we engineered a leakage-free hybrid system for precise gene expression controls in Fusobacterium nucleatum by integrating the xylose-inducible expression system with the theophylline-responsive riboswitch. This innovative method enables concurrent control of target gene expression at both transcription and translation initiation levels. Using luciferase and the indole-producing enzyme tryptophanase (TnaA) as reporters, we demonstrated that the hybrid system displays virtually no observable signal in the absence of inducers. We employed this system to express FtsX, a protein related to fusobacterial cytokinesis, in an …

Dpyd Pathogenic Variants Associated With Fluoropyrimidines Toxicity, Diana Cristina Pérez-Ibave, Noé Israel Oliva-García, Irasema Ramos-Martínez, Francisco Javier Villarreal Alvarado, Valeria Jimena Gómez Ordaz, Jonatán Isaí Cortes Alfaro, Carlos Horacio Burciaga-Flores, Juan Francisco González-Guerrero, Oscar Vidal-Gutiérrez, Maria De Lourdes Garza-Rodriguez

Research Symposium

Background: Genetic variants in dihydropyrimidine dehydrogenase gene (DPYD) coding for the key enzyme (DPD) of fluoropyrimidines (FPs) catabolism. DPYD contributes to the development of severe FPs-related toxicity, and pathogenic DPYD variants detection reduces side effects and complications associated with FP-toxicity. The allelic frequency of these variants in the Mexican population is currently unknown.

Methods: The study was carried out at the Centro Universitario Contra el Cáncer (CUCC) of the Universidad Autónoma de Nuevo León (UANL) in Monterrey México. Genomic DNA was isolated from 154 subjects using the QIAamp DNA Blood Midi kit (QIAGEN) following the manufacturer's recommendations. We …

Foxo Transcription Factors & Gene Expression, Larissa Barroso, Angelica M. Reyes, David Flores, Millat Jahan, Shania Pintor, Alma Lopez, Megan Keniry

Research Symposium

This paper attempts to highlight ForkHead box transcription factors (FOXO -1, -3, and -4) importance of subcellular localization in U87MG and myoblasts.

Synlight: A Bicistronic Strategy For Simultaneous Active Zone And Cell Labeling In The Drosophila Nervous System, Michael A. Aimino, Jesse Humenik, Michael J. Parisi, Juan Carlos Duhart, Timothy J. Mosca

Farber Institute for Neuroscience Faculty Papers

At synapses, chemical neurotransmission mediates the exchange of information between neurons, leading to complex movement, behaviors, and stimulus processing. The immense number and variety of neurons within the nervous system make discerning individual neuron populations difficult, necessitating the development of advanced neuronal labeling techniques. In Drosophila, Bruchpilot-Short and mCD8-GFP, which label presynaptic active zones and neuronal membranes, respectively, have been widely used to study synapse development and organization. This labeling is often achieved via the expression of 2 independent constructs by a single binary expression system, but expression can weaken when multiple transgenes are expressed by a single driver. Recent …