Digital Commons Network^™

Colorectal Cancer Murine Models: Initiation To Metastasis, Ramesh Pothuraju, Imran Khan, Maneesh Jain, Michael Bouvet, Mokenge Malafa, Hemant K Roy, Sushil Kumar, Surinder K Batra

Faculty, Staff and Students Publications

Despite significant advancements in prevention and treatment, colorectal cancer (CRC) remains the third leading cause of cancer-related deaths. Animal models, including xenografts, syngeneic, and genetically engineered, have emerged as indispensable tools in cancer research. These models offer a valuable platform to address critical questions regarding molecular pathogenesis and test therapeutic interventions before moving on to clinical trials. Advancements in CRC animal models have also facilitated the advent of personalized and precision medicine. Patient-derived xenografts and genetically engineered mice that mirror features of human tumors allow for tailoring treatments to specific CRC subtypes, improving treatment outcomes and quality of life. To …

Cd24 Negativity Reprograms Mitochondrial Metabolism To Pparα And Nf-Κb-Driven Fatty Acid Β-Oxidation In Triple-Negative Breast Cancer, Divya Murthy, Debasmita Dutta, Kuldeep S Attri, Tagari Samanta, Sukjin Yang, Kwang Hwa Jung, Sarah G Latario, Vasanta Putluri, Shixia Huang, Nagireddy Putluri, Jun Hyoung Park, Benny Abraham Kaipparettu

Faculty, Staff and Students Publications

CD24 is a well-characterized breast cancer (BC) stem cell (BCSC) marker. Primary breast tumor cells having CD24-negativity together with CD44-positivity is known to maintain high metastatic potential. However, the functional role of CD24 gene in triple-negative BC (TNBC), an aggressive subtype of BC, is not well understood. While the significance of CD24 in regulating immune pathways is well recognized in previous studies, the significance of CD24 low expression in onco-signaling and metabolic rewiring is largely unknown. Using CD24 knock-down and over-expression TNBC models, our in vitro and in vivo analysis suggest that CD24 is a tumor suppressor in metastatic TNBC. …

Innovation In Non-Invasive Diagnosis And Disease Monitoring For Meningiomas, Brianna Korte, Dimitrios Mathios

2020-Current year OA Pubs

Meningiomas are tumors of the central nervous system that vary in their presentation, ranging from benign and slow-growing to highly aggressive. The standard method for diagnosing and classifying meningiomas involves invasive surgery and can fail to provide accurate prognostic information. Liquid biopsy methods, which exploit circulating tumor biomarkers such as DNA, extracellular vesicles, micro-RNA, proteins, and more, offer a non-invasive and dynamic approach for tumor classification, prognostication, and evaluating treatment response. Currently, a clinically approved liquid biopsy test for meningiomas does not exist. This review provides a discussion of current research and the challenges of implementing liquid biopsy techniques for …

Bone Canonical Wnt Signaling Is Downregulated In Type 2 Diabetes And Associates With Higher Advanced Glycation End-Products (Ages) Content And Reduced Bone Strength, Giulia Leanza, Alec T Beeve, Erica L Scheller, Simon Y Tang, Roberto Civitelli, Nicola Napoli, Et Al.

2020-Current year OA Pubs

Type 2 diabetes (T2D) is associated with higher fracture risk, despite normal or high bone mineral density. We reported that bone formation genes (

Data-Driven Modeling Of Core Gene Regulatory Network Underlying Leukemogenesis In Idh Mutant Aml., Ataur Katebi, Xiaowen Chen, Daniel Ramirez, Sheng Li, Mingyang Lu

Faculty Research 2024

Acute myeloid leukemia (AML) is characterized by uncontrolled proliferation of poorly differentiated myeloid cells, with a heterogenous mutational landscape. Mutations in IDH1 and IDH2 are found in 20% of the AML cases. Although much effort has been made to identify genes associated with leukemogenesis, the regulatory mechanism of AML state transition is still not fully understood. To alleviate this issue, here we develop a new computational approach that integrates genomic data from diverse sources, including gene expression and ATAC-seq datasets, curated gene regulatory interaction databases, and mathematical modeling to establish models of context-specific core gene regulatory networks (GRNs) for a …

Altered Platelet-Megakaryocyte Endocytosis And Trafficking Of Albumin And Fibrinogen In Runx1 Haplodeficiency, Fabiola Del Carpio-Cano, Guangfen Mao, Lawrence E. Goldfinger, Jeremy Wurtzel, Liying Guan, Mohammad Afaque Alam, Kiwon Lee, Mortimer Poncz, A. Koneti Rao

Cardeza Foundation for Hematologic Research

Platelet α-granules have numerous proteins, some synthesized by megakaryocytes (MK) and others not synthesized but incorporated by endocytosis, an incompletely understood process in platelets/MK. Germ line RUNX1 haplodeficiency, referred to as familial platelet defect with predisposition to myeloid malignancies (FPDMMs), is associated with thrombocytopenia, platelet dysfunction, and granule deficiencies. In previous studies, we found that platelet albumin, fibrinogen, and immunoglobulin G (IgG) were decreased in a patient with FPDMM. We now show that platelet endocytosis of fluorescent-labeled albumin, fibrinogen, and IgG is decreased in the patient and his daughter with FPDMM. In megakaryocytic human erythroleukemia (HEL) cells, small interfering RNA …

Cardiovascular Disease Management With Sodium-Glucose Cotransporter-2 Inhibitors In Patients With Type 2 Diabetes: A Cardiology Primer, Allan Zhang, Ramsey Kalil, Alexander Marzec, Stephanie A Coulter, Salim Virani, Kershaw V Patel, Matthew W Segar

Faculty, Staff and Students Publications

Patients with type 2 diabetes face an elevated risk of cardiovascular disease. This review centers on sodium-glucose cotransporter-2 (SGLT2) inhibitors, a class of drugs that, according to a growing body of evidence, may have major potential for managing cardiovascular disease in patients with type 2 diabetes. This review presents findings from multiple clinical trials suggesting that SGLT2 inhibitors can not only serve as preventive therapeutic agents but also play a role in the active management of heart failure. The discussion includes the mechanism of action of SGLT2 inhibitors, emphasizing that they enhance urinary glucose excretion, which could lead to improved …

Arterial Spin-Labeling And Dsc Perfusion Metrics Improve Agreement In Neuroradiologists' Clinical Interpretations Of Posttreatment High-Grade Glioma Surveillance Mr Imaging-An Institutional Experience, Ghiam Yamin, Eric Tranvinh, Bryan A Lanzman, Elizabeth Tong, Syed S Hashmi, Chirag B Patel, Michael Iv

Faculty, Staff and Student Publications

Background and purpose: MR perfusion has shown value in the evaluation of posttreatment high-grade gliomas, but few studies have shown its impact on the consistency and confidence of neuroradiologists' interpretation in routine clinical practice. We evaluated the impact of adding MR perfusion metrics to conventional contrast-enhanced MR imaging in posttreatment high-grade glioma surveillance imaging.

Materials and methods: This retrospective study included 45 adults with high-grade gliomas who had posttreatment perfusion MR imaging. Four neuroradiologists assigned Brain Tumor Reporting and Data System scores for each examination on the basis of the interpretation of contrast-enhanced MR imaging and then after the addition …

Arid1a Orchestrates Swi/Snf-Mediated Sequential Binding Of Transcription Factors With Arid1a Loss Driving Pre-Memory B Cell Fate And Lymphomagenesis, Darko Barisic, Christopher R Chin, Cem Meydan, Matt Teater, Ioanna Tsialta, Coraline Mlynarczyk, Amy Chadburn, Xuehai Wang, Margot Sarkozy, Min Xia, Sandra E Carson, Santo Raggiri, Sonia Debek, Benedikt Pelzer, Ceyda Durmaz, Qing Deng, Priya Lakra, Martin Rivas, Christian Steidl, David W Scott, Andrew P Weng, Christopher E Mason, Michael R Green, Ari Melnick

Faculty, Staff and Student Publications

ARID1A, a subunit of the canonical BAF nucleosome remodeling complex, is commonly mutated in lymphomas. We show that ARID1A orchestrates B cell fate during the germinal center (GC) response, facilitating cooperative and sequential binding of PU.1 and NF-kB at crucial genes for cytokine and CD40 signaling. The absence of ARID1A tilts GC cell fate toward immature IgM+CD80-PD-L2- memory B cells, known for their potential to re-enter new GCs. When combined with BCL2 oncogene, ARID1A haploinsufficiency hastens the progression of aggressive follicular lymphomas (FLs) in mice. Patients with FL with ARID1A-inactivating mutations preferentially display an immature memory B cell-like state with …

Smarca4 Is A Haploinsufficient B Cell Lymphoma Tumor Suppressor That Fine-Tunes Centrocyte Cell Fate Decisions, Qing Deng, Priya Lakra, Panhong Gou, Haopeng Yang, Cem Meydan, Matthew Teater, Christopher Chin, Wenchao Zhang, Tommy Dinh, Usama Hussein, Xubin Li, Estela Rojas, Weiguang Liu, Patrick K Reville, Atish Kizhakeyil, Darko Barisic, Sydney Parsons, Ashley Wilson, Jared Henderson, Brooks Scull, Channabasavaiah Gurumurthy, Francisco Vega, Amy Chadburn, Branko Cuglievan, Nader Kim El-Mallawany, Carl Allen, Christopher Mason, Ari Melnick, Michael R Green

Faculty, Staff and Student Publications

SMARCA4 encodes one of two mutually exclusive ATPase subunits in the BRG/BRM associated factor (BAF) complex that is recruited by transcription factors (TFs) to drive chromatin accessibility and transcriptional activation. SMARCA4 is among the most recurrently mutated genes in human cancer, including ∼30% of germinal center (GC)-derived Burkitt lymphomas. In mice, GC-specific Smarca4 haploinsufficiency cooperated with MYC over-expression to drive lymphomagenesis. Furthermore, monoallelic Smarca4 deletion drove GC hyperplasia with centroblast polarization via significantly increased rates of centrocyte recycling to the dark zone. Mechanistically, Smarca4 loss reduced the activity of TFs that are activated in centrocytes to drive GC-exit, including SPI1 …

Single-Cell Systems Pharmacology Identifies Development-Driven Drug Response And Combination Therapy In B Cell Acute Lymphoblastic Leukemia, Xin Huang, Yizhen Li, Jingliao Zhang, Lei Yan, Huanbin Zhao, Liang Ding, Sheetal Bhatara, Xu Yang, Satoshi Yoshimura, Wenjian Yang, Seth E Karol, Hiroto Inaba, Charles Mullighan, Mark Litzow, Xiaofan Zhu, Yingchi Zhang, Wendy Stock, Nitin Jain, Elias Jabbour, Steven M Kornblau, Marina Konopleva, Ching-Hon Pui, Elisabeth Paietta, William Evans, Jiyang Yu, Jun J Yang

Faculty, Staff and Student Publications

Leukemia can arise at various stages of the hematopoietic differentiation hierarchy, but the impact of developmental arrest on drug sensitivity is unclear. Applying network-based analyses to single-cell transcriptomes of human B cells, we define genome-wide signaling circuitry for each B cell differentiation stage. Using this reference, we comprehensively map the developmental states of B cell acute lymphoblastic leukemia (B-ALL), revealing its strong correlation with sensitivity to asparaginase, a commonly used chemotherapeutic agent. Single-cell multi-omics analyses of primary B-ALL blasts reveal marked intra-leukemia heterogeneity in asparaginase response: resistance is linked to pre-pro-B-like cells, with sensitivity associated with the pro-B-like population. By …

Timing Along The Cardiac Cycle Modulates Neural Signals Of Reward-Based Learning, Elsa F. Fouragnan, Billy Hosking, Yin Cheung, Brooke Prakash, Matthew Rushworth, Alejandra Sel

School of Psychology

Natural fluctuations in cardiac activity modulate brain activity associated with sensory stimuli, as well as perceptual decisions about low magnitude, near-threshold stimuli. However, little is known about the relationship between fluctuations in heart activity and other internal representations. Here we investigate whether the cardiac cycle relates to learning-related internal representations – absolute and signed prediction errors. We combined machine learning techniques with electroencephalography with both simple, direct indices of task performance and computational model-derived indices of learning. Our results demonstrate that just as people are more sensitive to low magnitude, near-threshold sensory stimuli in certain cardiac phases, so are they …

An In Vitro Neurogenetics Platform For Precision Disease Modeling In The Mouse., Daniel Cortes, Mélanie Escudero, Austin C Korgan, Arojit Mitra, Alyssa Edwards, Selcan Aydin, Steven C. Munger, Kevin Charland, Zhong-Wei Zhang, Kristen M S O'Connell, Laura G Reinholdt, Martin Pera

Faculty Research 2024

The power and scope of disease modeling can be markedly enhanced through the incorporation of broad genetic diversity. The introduction of pathogenic mutations into a single inbred mouse strain sometimes fails to mimic human disease. We describe a cross-species precision disease modeling platform that exploits mouse genetic diversity to bridge cell-based modeling with whole organism analysis. We developed a universal protocol that permitted robust and reproducible neural differentiation of genetically diverse human and mouse pluripotent stem cell lines and then carried out a proof-of-concept study of the neurodevelopmental gene DYRK1A. Results in vitro reliably predicted the effects of genetic background …

Csf Biomarkers Of Immune Activation And Alzheimer's Disease For Predicting Cognitive Impairment Risk In The Elderly, Francis Shue, Rachel Hendrix, Jason Ulrich, Rachel L Henson, William Knight, Chengjie Xiong, Jigyasha Timsina, Yun Ju Sung, Carlos Cruchaga, David M Holtzman, Et Al.

2020-Current year OA Pubs

The immune system substantially influences age-related cognitive decline and Alzheimer's disease (AD) progression, affected by genetic and environmental factors. In a Mayo Clinic Study of Aging cohort, we examined how risk factors like APOE genotype, age, and sex affect inflammatory molecules and AD biomarkers in cerebrospinal fluid (CSF). Among cognitively unimpaired individuals over 65 (

Human Brain Glycoform Coregulation Network And Glycan Modification Alterations In Alzheimer's Disease, Qi Zhang, Cheng Ma, Lih-Shen Chin, Sheng Pan, Lian Li

Faculty, Staff and Student Publications

Despite the importance of protein glycosylation to brain health, current knowledge of glycosylated proteoforms or glycoforms in human brain and their alterations in Alzheimer's disease (AD) is limited. Here, we report a proteome-wide glycoform profiling study of human AD and control brains using intact glycopeptide-based quantitative glycoproteomics coupled with systems biology. Our study identified more than 10,000 human brain N-glycoforms from nearly 1200 glycoproteins and uncovered disease signatures of altered glycoforms and glycan modifications, including reduced sialylation and N-glycan branching and elongation as well as elevated mannosylation and N-glycan truncation in AD. Network analyses revealed a higher-order organization of brain …

Unsupervised Deep Representation Learning Enables Phenotype Discovery For Genetic Association Studies Of Brain Imaging, Khush Patel, Ziqian Xie, Hao Yuan, Sheikh Muhammad Saiful Islam, Yaochen Xie, Wei He, Wanheng Zhang, Assaf Gottlieb, Han Chen, Luca Giancardo, Alexander Knaack, Evan Fletcher, Myriam Fornage, Shuiwang Ji, Degui Zhi

Faculty, Staff and Student Publications

Understanding the genetic architecture of brain structure is challenging, partly due to difficulties in designing robust, non-biased descriptors of brain morphology. Until recently, brain measures for genome-wide association studies (GWAS) consisted of traditionally expert-defined or software-derived image-derived phenotypes (IDPs) that are often based on theoretical preconceptions or computed from limited amounts of data. Here, we present an approach to derive brain imaging phenotypes using unsupervised deep representation learning. We train a 3-D convolutional autoencoder model with reconstruction loss on 6130 UK Biobank (UKBB) participants' T1 or T2-FLAIR (T2) brain MRIs to create a 128-dimensional representation known as Unsupervised Deep learning …

Discovery Of A Small-Molecule Inhibitor That Traps Polθ On Dna And Synergizes With Parp Inhibitors, William Fried, Mrityunjay Tyagi, Leonid Minakhin, Gurushankar Chandramouly, Taylor Tredinnick, Mercy Ramanjulu, William Auerbacher, Marissa L Calbert, Timur Rusanov, Trung Hoang, Nikita Borisonnik, Robert Betsch, John Krais, Yifan Wang, Umeshkumar Vekariya, John Gordon, George Morton, Tatiana Kent, Tomasz Skorski, Neil Johnson, Wayne Childers, Xiaojiang Chen, Richard Pomerantz

Department of Biochemistry and Molecular Biology Faculty Papers

The DNA damage response (DDR) protein DNA Polymerase θ (Polθ) is synthetic lethal with homologous recombination (HR) factors and is therefore a promising drug target in BRCA1/2 mutant cancers. We discover an allosteric Polθ inhibitor (Polθi) class with 4-6 nM IC₅₀ that selectively kills HR-deficient cells and acts synergistically with PARP inhibitors (PARPi) in multiple genetic backgrounds. X-ray crystallography and biochemistry reveal that Polθi selectively inhibits Polθ polymerase (Polθ-pol) in the closed conformation on B-form DNA/DNA via an induced fit mechanism. In contrast, Polθi fails to inhibit Polθ-pol catalytic activity on A-form DNA/RNA in which the enzyme binds in …

Intestinal Cell Diversity And Treatment Responses In A Parasitic Nematode At Single Cell Resolution, Rahul Tyagi, Bruce A Rosa, Amanda Swain, Maxim N Artyomov, Douglas P Jasmer, Makedonka Mitreva

2020-Current year OA Pubs

BACKGROUND: Parasitic nematodes, significant pathogens for humans, animals, and plants, depend on diverse organ systems for intra-host survival. Understanding the cellular diversity and molecular variations underlying these functions holds promise for developing novel therapeutics, with specific emphasis on the neuromuscular system's functional diversity. The nematode intestine, crucial for anthelmintic therapies, exhibits diverse cellular phenotypes, and unraveling this diversity at the single-cell level is essential for advancing knowledge in anthelmintic research across various organ systems.

RESULTS: Here, using novel single-cell transcriptomics datasets, we delineate cellular diversity within the intestine of adult female Ascaris suum, a parasitic nematode species that infects animals …

Vista Checkpoint Inhibition By Ph-Selective Antibody Sns-101 With Optimized Safety And Pharmacokinetic Profiles Enhances Pd-1 Response, Thomas Thisted, Yoshiko Takeuchi, Robert D Schreiber, Et Al.

2020-Current year OA Pubs

VISTA, an inhibitory myeloid-T-cell checkpoint, holds promise as a target for cancer immunotherapy. However, its effective targeting has been impeded by issues such as rapid clearance and cytokine release syndrome observed with previous VISTA antibodies. Here we demonstrate that SNS-101, a newly developed pH-selective VISTA antibody, addresses these challenges. Structural and biochemical analyses confirmed the pH-selectivity and unique epitope targeted by SNS-101. These properties confer favorable pharmacokinetic and safety profiles on SNS-101. In syngeneic tumor models utilizing human VISTA knock-in mice, SNS-101 shows in vivo efficacy when combined with a PD-1 inhibitor, modulates cytokine and chemokine signaling, and alters the …

First-In-Human Phase I Study Of Tinengotinib (Tt-00420), A Multiple Kinase Inhibitor, As A Single Agent In Patients With Advanced Solid Tumors, Sarina A Piha-Paul, Binghe Xu, Ecaterina E Dumbrava, Siqing Fu, Daniel D Karp, Funda Meric-Bernstam, David S Hong, Jordi A Rodon, Apostolia M Tsimberidou, Kanwal Raghav, Jaffer A Ajani, Anthony P Conley, Frank Mott, Ying Fan, Jean Fan, Peng Peng, Hui Wang, Shumao Ni, Caixia Sun, Xiaoyan Qiang, Wendy J Levin, Brenda Ngo, Qinhua Cindy Ru, Frank Wu, Milind M Javle

Faculty, Staff and Student Publications

PURPOSE: This first-in-human phase I dose-escalation study evaluated the safety, pharmacokinetics, and efficacy of tinengotinib (TT-00420), a multi-kinase inhibitor targeting fibroblast growth factor receptors 1-3 (FGFRs 1-3), Janus kinase 1/2, vascular endothelial growth factor receptors, and Aurora A/B, in patients with advanced solid tumors.

PATIENTS AND METHODS: Patients received tinengotinib orally daily in 28-day cycles. Dose escalation was guided by Bayesian modeling using escalation with overdose control. The primary objective was to assess dose-limiting toxicities (DLTs), maximum tolerated dose (MTD), and dose recommended for dose expansion (DRDE). Secondary objectives included pharmacokinetics and efficacy.

RESULTS: Forty-eight patients were enrolled (dose escalation, …

Somatic Mutations In Normal Tissues: Calm Before The Storm, Zahraa Rahal, Paul Scheet, Humam Kadara

Faculty, Staff and Student Publications

We explore the phenomenon of somatic mutations, including those in cancer driver genes, that are present in healthy, normal-appearing tissues and their potential implications for cancer development. We also examine the landscape of these somatic mutations, discuss the role of clonal cell competition and external factors like inflammation in enhancing the fitness of mutant clones, and conclude by considering how understanding these mutations will aid in prevention and/or interception of cancer.

The Hallmarks Of Precancer, Mary M Stangis, Zhengyi Chen, Jimin Min, Sarah E Glass, Jordan O Jackson, Megan D Radyk, Xen Ping Hoi, W Nathaniel Brennen, Ming Yu, Huy Q Dinh, Robert J Coffey, Martha J Shrubsole, Keith S Chan, William M Grady, Srinivasan Yegnasubramanian, Costas A Lyssiotis, Anirban Maitra, Richard B Halberg, Neelendu Dey, Ken S Lau

Faculty, Staff and Student Publications

Research on precancers, as defined as at-risk tissues and early lesions, is of high significance given the effectiveness of early intervention. We discuss the need for risk stratification to prevent overtreatment, an emphasis on the role of genetic and epigenetic aging when considering risk, and the importance of integrating macroenvironmental risk factors with molecules and cells in lesions and at-risk normal tissues for developing effective intervention and health policy strategies.

T-Cell Dysfunctions In Myelodysplastic Syndromes, Juan Jose Rodriguez-Sevilla, Simona Colla

Faculty, Staff and Student Publications

Escape from immune surveillance is a hallmark of cancer. Immune deregulation caused by intrinsic and extrinsic cellular factors, such as altered T-cell functions, leads to immune exhaustion, loss of immune surveillance, and clonal proliferation of tumoral cells. The T-cell immune system contributes to the pathogenesis, maintenance, and progression of myelodysplastic syndrome (MDS). Here, we comprehensively reviewed our current biological knowledge of the T-cell compartment in MDS and recent advances in the development of immunotherapeutic strategies, such as immune checkpoint inhibitors and T-cell- and antibody-based adoptive therapies that hold promise to improve the outcome of patients with MDS.

De Novo Variants In Fryl Are Associated With Developmental Delay, Intellectual Disability, And Dysmorphic Features, Xueyang Pan, Alice M Tao, Shenzhao Lu, Mengqi Ma, Shabab B Hannan, Rachel Slaugh, Sarah Drewes Williams, Lauren O'Grady, Oguz Kanca, Richard Person, Melissa T Carter, Konrad Platzer, Franziska Schnabel, Rami Abou Jamra, Amy E Roberts, Jane W Newburger, Anya Revah-Politi, Jorge L Granadillo, Alexander P A Stegmann, Margje Sinnema, Andrea Accogli, Vincenzo Salpietro, Valeria Capra, Lina Ghaloul-Gonzalez, Martina Brueckner, Marleen E H Simon, David A Sweetser, Kevin E Glinton, Susan E Kirk, Baylor College Of Medicine Center For Precision Medicine Models, Michael F Wangler, Shinya Yamamoto, Wendy K Chung, Hugo J Bellen

Faculty, Staff and Students Publications

FRY-like transcription coactivator (FRYL) belongs to a Furry protein family that is evolutionarily conserved from yeast to humans. The functions of FRYL in mammals are largely unknown, and variants in FRYL have not previously been associated with a Mendelian disease. Here, we report fourteen individuals with heterozygous variants in FRYL who present with developmental delay, intellectual disability, dysmorphic features, and other congenital anomalies in multiple systems. The variants are confirmed de novo in all individuals except one. Human genetic data suggest that FRYL is intolerant to loss of function (LoF). We find that the fly FRYL ortholog, furry (fry), is …

Next Directions In The Neuroscience Of Cancers Arising Outside The Cns, Moran Amit, Corina Anastasaki, Robert Dantzer, Ihsan Ekin Demir, Benjamin Deneen, Karen O Dixon, Mikala Egeblad, Erin M Gibson, Shawn L Hervey-Jumper, Hubert Hondermarck, Claire Magnon, Michelle Monje, Shorook Na'ara, Yuan Pan, Elizabeth A Repasky, Nicole N Scheff, Erica K Sloan, Sebastien Talbot, Kevin J Tracey, Lloyd C Trotman, Manuel Valiente, Linda Van Aelst, Varun Venkataramani, Humsa S Venkatesh, Paola D Vermeer, Frank Winkler, Richard J Wong, David H Gutmann, Jeremy C Borniger

Faculty, Staff and Students Publications

The field of cancer neuroscience has begun to define the contributions of nerves to cancer initiation and progression; here, we highlight the future directions of basic and translational cancer neuroscience for malignancies arising outside of the central nervous system.

Bi-Allelic Acbd6 Variants Lead To A Neurodevelopmental Syndrome With Progressive And Complex Movement Disorders, Rauan Kaiyrzhanov, Aboulfazl Rad, Sheng-Jia Lin, Aida Bertoli-Avella, Wouter W Kallemeijn, Annie Godwin, Maha S Zaki, Kevin Huang, Tracy Lau, Cassidy Petree, Stephanie Efthymiou, Ehsan Ghayoor Karimiani, Maja Hempel, Elizabeth A Normand, Sabine Rudnik-Schöneborn, Ulrich A Schatz, Marc P Baggelaar, Muhammad Ilyas, Tipu Sultan, Javeria Raza Alvi, Manizha Ganieva, Ben Fowler, Ruxandra Aanicai, Gulsen Akay Tayfun, Abdulaziz Al Saman, Abdulrahman Alswaid, Nafise Amiri, Nilufar Asilova, Vorasuk Shotelersuk, Patra Yeetong, Matloob Azam, Meisam Babaei, Gholamreza Bahrami Monajemi, Pouria Mohammadi, Saeed Samie, Selina Husna Banu, Jorge Pinto Basto, Fanny Kortüm, Mislen Bauer, Peter Bauer, Christian Beetz, Masoud Garshasbi, Awatif Hameed Issa, Wafaa Eyaid, Hind Ahmed, Narges Hashemi, Kazem Hassanpour, Isabella Herman, Sherozjon Ibrohimov, Ban A Abdul-Majeed, Maria Imdad, Maksudjon Isrofilov, Qassem Kaiyal, Suliman Khan, Brian Kirmse, Janet Koster, Charles Marques Lourenço, Tadahiro Mitani, Oana Moldovan, David Murphy, Maryam Najafi, Davut Pehlivan, Maria Eugenia Rocha, Vincenzo Salpietro, Miriam Schmidts, Adel Shalata, Mohammad Mahroum, Jawabreh Kassem Talbeya, Robert W Taylor, Dayana Vazquez, Annalisa Vetro, Hans R Waterham, Mashaya Zaman, Tina A Schrader, Wendy K Chung, Renzo Guerrini, James R Lupski, Joseph Gleeson, Mohnish Suri, Yalda Jamshidi, Kailash P Bhatia, Barbara Vona, Michael Schrader, Mariasavina Severino, Matthew Guille, Edward W Tate, Gaurav K Varshney, Henry Houlden, Reza Maroofian

Faculty, Staff and Students Publications

The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Using exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with myristic acid alkyne …

Induction Of Viral Mimicry Upon Loss Of Dhx9 And Adar1 In Breast Cancer Cells, Kyle A Cottrell, Sua Ryu, Jackson R Pierce, Luisangely Soto Torres, Holly E Bohlin, Angela M Schab, Jason D Weber

2020-Current year OA Pubs

UNLABELLED: Detection of viral double-stranded RNA (dsRNA) is an important component of innate immunity. However, many endogenous RNAs containing double-stranded regions can be misrecognized and activate innate immunity. The IFN-inducible ADAR1-p150 suppresses dsRNA sensing, an essential function for adenosine deaminase acting on RNA 1 (ADAR1) in many cancers, including breast. Although ADAR1-p150 has been well established in this role, the functions of the constitutively expressed ADAR1-p110 isoform are less understood. We used proximity labeling to identify putative ADAR1-p110-interacting proteins in breast cancer cell lines. Of the proteins identified, the RNA helicase DHX9 was of particular interest. Knockdown of DHX9 in …

Antibody-Mediated Targeting Of Human Microglial Leukocyte Ig-Like Receptor B4 Attenuates Amyloid Pathology In A Mouse Model, Jinchao Hou, Yun Chen, Zhangying Cai, Gyu Seong Heo, Carla M Yuede, Zuoxu Wang, Kent Lin, Fareeha Saadi, Tihana Trsan, Aivi T Nguyen, Eleni Constantopoulos, Rachel A Larsen, Yiyang Zhu, Nicole D Wagner, Nolan Mclaughlin, Xinyi Cynthia Kuang, Alexander D Barrow, Dian Li, Yingyue Zhou, Shoutang Wang, Susan Gilfillan, Michael L Gross, Simone Brioschi, Yongjian Liu, David M Holtzman, Marco Colonna

The Brown Foundation: Institute of Molecular Medicine

Microglia help limit the progression of Alzheimer’s disease (AD) by constraining amyloid-β (Aβ) pathology, effected through a balance of activating and inhibitory intracellular signals delivered by distinct cell surface receptors. Human leukocyte Ig-like receptor B4 (LILRB4) is an inhibitory receptor of the immunoglobulin (Ig) superfamily that is expressed on myeloid cells and recognizes apolipoprotein E (ApoE) among other ligands. Here, we find that LILRB4 is highly expressed in microglia of patients with AD. Using mice that accumulate Aβ and carry a transgene encompassing a portion of the LILR region that includes LILRB4, we corroborated abundant LILRB4 expression in microglia …

Oncogenic Oral Human Papillomavirus Clearance Patterns Over 10 Years, Gypsyamber D'Souza, Sakshi R Tewari, Tanya Troy, Jennifer Webster-Cyriaque, Dorothy J Wiley, Cecile Delille Lahiri, Frank Joseph Palella, Maura L Gillison, Howard D Strickler, Linda Struijk, Tim Waterboer, Ken Ho, Jennafer Kwait, Jason Lazar, Kathleen M Weber, Carole Fakhry

Faculty, Staff and Student Publications

Background: Effective screening for oropharyngeal cancer is lacking. Four oncogenic HPV clearance definitions were explored to understand long-term natural history for persistent oncogenic oral HPV (oncHPV), the precursor of oropharyngeal cancer.

Methods: Prospective multicenter cohort of participants living with/at-risk for HIV, with oral rinse and gargle samples collected every 6 to 12 months for up to 10 years and tested for oncHPV. HPV clearance definitions included 1 (clear1), 2 (clear2), 3 (clear3) consecutive negatives, or being negative at last two visits (clearlast).

Results: Median time to clearance of oncHPV exceeded 2 years for conservative definitions (clear3: 2.38, clearlast: 2.43), but …

Artificial Intelligence Predictive Analytics In Heart Failure: Results Of The Pilot Phase Of A Pragmatic Randomized Clinical Trial, Konstantinos Sideris, Charlene R Weir, Carsten Schmalfuss, Heather Hanson, Matt Pipke, Po-He Tseng, Neil Lewis, Karim Sallam, Biykem Bozkurt, Thomas Hanff, Richard Schofield, Karen Larimer, Christos P Kyriakopoulos, Iosif Taleb, Lina Brinker, Tempa Curry, Cheri Knecht, Jorie M Butler, Josef Stehlik

Faculty, Staff and Students Publications

OBJECTIVES: We conducted an implementation planning process during the pilot phase of a pragmatic trial, which tests an intervention guided by artificial intelligence (AI) analytics sourced from noninvasive monitoring data in heart failure patients (LINK-HF2).

MATERIALS AND METHODS: A mixed-method analysis was conducted at 2 pilot sites. Interviews were conducted with 12 of 27 enrolled patients and with 13 participating clinicians. iPARIHS constructs were used for interview construction to identify workflow, communication patterns, and clinician's beliefs. Interviews were transcribed and analyzed using inductive coding protocols to identify key themes. Behavioral response data from the AI-generated notifications were collected.

RESULTS: Clinicians …