Neurosciences Commons^™

Tumor Treating Fields Suppress Tumor Cell Growth And Neurologic Decline In Models Of Spinal Metastases, Daniel Ledbetter, Romulo Augusto Andrade De Almeida, Xizi Wu, Ariel Naveh, Chirag B Patel, Queena Gonzalez, Thomas H Beckham, Robert North, Laurence Rhines, Jing Li, Amol Ghia, David Aten, Claudio Tatsui, Christopher Alvarez-Breckenridge

Faculty, Staff and Student Publications

Spinal metastases can result in severe neurologic compromise and decreased overall survival. Despite treatment advances, local disease progression is frequent, highlighting the need for novel therapies. Tumor treating fields (TTFields) impair tumor cell replication and are influenced by properties of surrounding tissue. We hypothesized that bone's dielectric properties will enhance TTFields-mediated suppression of tumor growth in spinal metastasis models. Computational modeling of TTFields intensity was performed following surgical resection of a spinal metastasis and demonstrated enhanced TTFields intensity within the resected vertebral body. Additionally, luciferase-tagged human KRIB osteosarcoma and A549 lung adenocarcinoma cell lines were cultured in demineralized bone grafts …

Mapping Sca1 Regional Vulnerabilities Reveals Neural And Skeletal Muscle Contributions To Disease, Lisa Duvick, W Michael Southern, Kellie A Benzow, Zoe N Burch, Hillary P Handler, Jason S Mitchell, Hannah Kuivinen, Udaya Gadiparthi, Praseuth Yang, Alyssa Soles, Carrie A Sheeler, Orion Rainwater, Shannah Serres, Erin B Lind, Tessa Nichols-Meade, Yun You, Brennon O'Callaghan, Huda Y Zoghbi, Marija Cvetanovic, Vanessa C Wheeler, James M Ervasti, Michael D Koob, Harry T Orr

Duncan NRI Faculty and Staff Publications

Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by an expanded polyglutamine tract in the widely expressed ataxin-1 (ATXN1) protein. To elucidate anatomical regions and cell types that underlie mutant ATXN1-induced disease phenotypes, we developed a floxed conditional knockin mouse (f-ATXN1146Q/2Q) with mouse Atxn1 coding exons replaced by human ATXN1 exons encoding 146 glutamines. f-ATXN1146Q/2Q mice manifested SCA1-like phenotypes including motor and cognitive deficits, wasting, and decreased survival. Central nervous system (CNS) contributions to disease were revealed using f-ATXN1146Q/2Q;Nestin-Cre mice, which showed improved rotarod, open field, and Barnes maze performance by 6-12 weeks of age. In contrast, …

A Tough Bioadhesive Hydrogel Supports Sutureless Sealing Of The Dural Membrane In Porcine And Ex Vivo Human Tissue, Kyle C Wu, Benjamin R Freedman, Phoebe S Kwon, Matthew Torre, Daniel O Kent, Wenya Linda Bi, David J Mooney

Duncan NRI Faculty and Staff Publications

Complete sequestration of central nervous system tissue and cerebrospinal fluid by the dural membrane is fundamental to maintaining homeostasis and proper organ function, making reconstruction of this layer an essential step during neurosurgery. Primary closure of the dura by suture repair is the current standard, despite facing technical, microenvironmental, and anatomic challenges. Here, we apply a mechanically tough hydrogel paired with a bioadhesive for intraoperative sealing of the dural membrane in rodent, porcine, and human central nervous system tissue. Tensile testing demonstrated that this dural tough adhesive (DTA) exhibited greater toughness with higher maximum stress and stretch compared with commercial …

Antioxidant Responses And Phytochemical Accumulation In Raphanus Species Sprouts Through Elicitors And Predictive Models Under High Temperature Stress, María-Trinidad Toro, Roberto Fustos-Toribio, Jaime Ortiz, José Becerra, Nelson Zapata, María Dolores López-Belchí

Faculty, Staff and Students Publications

Crop production is being impacted by higher temperatures, which can decrease food yield and pose a threat to human nutrition. In the current study, edible and wild radish sprouts were exposed to elevated growth temperatures along with the exogenous application of various elicitors to activate defense mechanisms. Developmental traits, oxidative damage, glucosinolate and anthocyanin content, and antioxidant capacity were evaluated alongside the development of a predictive model. A combination of four elicitors (citric acid, methyl jasmonate—MeJa, chitosan, and K2SO4) and high temperatures were applied. The accumulation of bioactives was significantly enhanced through the application of two elicitors, K2SO4 and methyl …

A Structured, Journal-Led Peer-Review Mentoring Program Enhances Peer Review Training, Ariel Maia Lyons-Warren, Whitley W Aamodt, Kathleen M Pieper, Roy E Strowd

Faculty, Staff and Students Publications

BACKGROUND: Peer review is essential to the advancement of knowledge. However, training on how to conduct peer review is limited, unorganized, and not well studied. Thus, we sought to determine if a structured mentored peer-review program improved peer review training as measured by multiple quantitative and qualitative assessments.

METHODS: This pre-post intervention study enrolled 55 mentees across 5 cohorts from 2020 to 2023. Each cohort completed pre-program evaluations, participated in 2 mentored reviews, and completed post-program evaluations over 6 months. Mentors and mentees completed pre-program demographic and review experience questionnaires. Outcome measures included (1) total and sub-scores on the modified …

Heterogeneity And Overlap In The Continuum Of Linguistic Profile Of Logopenic And Semantic Variants Of Primary Progressive Aphasia: A Profile Analysis Based On Multidimensional Scaling Study, Gaia Chiara Santi, Francesca Conca, Valentina Esposito, Cristina Polito, Silvia Paola Caminiti, Cecilia Boccalini, Carmen Morinelli, Valentina Berti, Salvatore Mazzeo, Valentina Bessi, Alessandra Marcone, Sandro Iannaccone, Se-Kang Kim, Sandro Sorbi, Daniela Perani, Stefano F Cappa, Eleonora Catricalà

Faculty, Staff and Students Publications

BACKGROUND: Primary progressive aphasia (PPA) diagnostic criteria underestimate the complex presentation of semantic (sv) and logopenic (lv) variants, in which symptoms partially overlap, and mixed clinical presentation (mixed-PPA) and heterogenous profile (lvPPA +) are frequent. Conceptualization of similarities and differences of these clinical conditions is still scarce.

METHODS: Lexical, semantic, phonological, and working memory errors from nine language tasks of sixty-seven PPA were analyzed using Profile Analysis based on Multidimensional Scaling, which allowed us to create a distributed representation of patients' linguistic performance in a shared space. Patients had been studied with [

RESULTS: Patients' profiles were distributed across a …

Variants In Zfx Are Associated With An X-Linked Neurodevelopmental Disorder With Recurrent Facial Gestalt\, James L Shepherdson, Katie Hutchison, Dilan Wellalage Don, George Mcgillivray, Tae-Ik Choi, Carolyn A Allan, David J Amor, Siddharth Banka, Donald G Basel, Laura D Buch, Deanna Alexis Carere, Renée Carroll, Jill Clayton-Smith, Ali Crawford, Morten Dunø, Laurence Faivre, Christopher P Gilfillan, Nina B Gold, Karen W Gripp, Emma Hobson, Alexander M Holtz, A Micheil Innes, Bertrand Isidor, Adam Jackson, Panagiotis Katsonis, Leila Amel Riazat Kesh, Genomics England Research Consortium;, Sébastien Küry, François Lecoquierre, Paul Lockhart, Julien Maraval, Naomichi Matsumoto, Julie Mccarrier, Josephine Mccarthy, Noriko Miyake, Lip Hen Moey, Andrea H Németh, Elsebet Østergaard, Rushina Patel, Kate Pope, Jennifer E Posey, Rhonda E Schnur, Marie Shaw, Elliot Stolerman, Julie P Taylor, Erin Wadman, Emma Wakeling, Susan M White, Lawrence C Wong, James R Lupski, Olivier Lichtarge, Mark A Corbett, Jozef Gecz, Charles M Nicolet, Peggy J Farnham, Cheol-Hee Kim, Marwan Shinawi

Duncan NRI Faculty and Staff Publications

Pathogenic variants in multiple genes on the X chromosome have been implicated in syndromic and non-syndromic intellectual disability disorders. ZFX on Xp22.11 encodes a transcription factor that has been linked to diverse processes including oncogenesis and development, but germline variants have not been characterized in association with disease. Here, we present clinical and molecular characterization of 18 individuals with germline ZFX variants. Exome or genome sequencing revealed 11 variants in 18 subjects (14 males and 4 females) from 16 unrelated families. Four missense variants were identified in 11 subjects, with seven truncation variants in the remaining individuals. Clinical findings included …

Neural Correlates Of Fear Extinction: Investing The Impact Of Puberty And Sex In Children And Adolescents Through Neuroimaging, Sneha Bhargava, Clara Zundel, Samantha Ely, Carmen Carpenter, Reem Tamimi, Leah Gowatch, Mackenna Shampine, Emilie-Clare O'Mara, Jovan Jande, Shravya Chanamolu, Ahmad Almaat, Hilary Marusak

Medical Student Research Symposium

Fear-based disorders, including anxiety and posttraumatic stress disorder, are more prevalent in females than males. Steroid hormones (e.g., estradiol) are involved in fear extinction learning and later recall—a process implicated in the pathophysiology of fear-based disorders. Fear-based disorders commonly emerge during the transition from childhood to adolescence, a period marked by the onset of puberty and a natural increase of steroid hormones. Here, we examined the effects of puberty, sex, and their interaction on extinction recall and underlying neural circuitry in youth. Eighty-five youth (6-17 years, 46% female) completed a two-day Pavlovian fear extinction paradigm while undergoing functional magnetic resonance …

Epithelial And Mesenchymal Olfactory Stem Cells Gathered With Minimally-Invasive Micro-Brush, Tyler Petersen

Medical Student Research Symposium

Spinal cord injury (SCI) causes devastating lifestyle and financial consequences for the patient. Treatment strategies emphasize neuroprotection, but not regeneration. In this regard, stem cells are an innovative field of study that has the potential to regenerate neural tissue, thereby increasing a person’s ability to regain function. The purpose of this project is two-fold: to attain olfactory stem cells located in the nasal canal in a minimally-invasive way and to gather neural cells from the epithelium and mesenchymal cells in the lamina propria. Cells were gathered with sterile nasal micro-brushes, stored, and grown in flasks. After cells reached confluency, they …

Timing Of Decompressive Surgery In Patients With Acute Spinal Cord Injury: Systematic Review Update, Michael G Fehlings, Laureen D Hachem, Lindsay A Tetreault, Andrea C Skelly, Joseph R Dettori, Erika D Brodt, Shay Stabler-Morris, Britt J Redick, Nathan Evaniew, Allan R Martin, Benjamin Davies, Farzin Farahbakhsh, James D Guest, Daniel Graves, Radha Korupolu, Stephen L Mckenna, Brian K Kwon

Faculty, Staff and Student Publications

STUDY DESIGN: Systematic review and meta-analysis.

OBJECTIVE: Surgical decompression is a cornerstone in the management of patients with traumatic spinal cord injury (SCI); however, the influence of the timing of surgery on neurological recovery after acute SCI remains controversial. This systematic review aims to summarize current evidence on the effectiveness, safety, and cost-effectiveness of early (≤24 hours) or late (>24 hours) surgery in patients with acute traumatic SCI for all levels of the spine. Furthermore, this systematic review aims to evaluate the evidence with respect to the impact of ultra-early surgery (earlier than 24 hours from injury) on these …

Heterozygous Map3k20 Variants Cause Ectodermal Dysplasia, Craniosynostosis, Sensorineural Hearing Loss, And Limb Anomalies, Daniel Brooks, Elizabeth Burke, Sukyeong Lee, Tanya N Eble, Melanie O'Leary, Ikeoluwa Osei-Owusu, Heidi L Rehm, Shweta U Dhar, Lisa Emrick, David Bick, Michelle Nehrebecky, Ellen Macnamara, Dídac Casas-Alba, Judith Armstrong, Carolina Prat, Antonio F Martínez-Monseny, Francesc Palau, Pengfei Liu, David Adams, Undiagnosed Diseases Network, Seema Lalani, Jill A Rosenfeld, Lindsay C Burrage

Faculty, Staff and Students Publications

Biallelic pathogenic variants in MAP3K20, which encodes a mitogen-activated protein kinase, are a rare cause of split-hand foot malformation (SHFM), hearing loss, and nail abnormalities or congenital myopathy. However, heterozygous variants in this gene have not been definitively associated with a phenotype. Here, we describe the phenotypic spectrum associated with heterozygous de novo variants in the linker region between the kinase domain and leucine zipper domain of MAP3K20. We report five individuals with diverse clinical features, including craniosynostosis, limb anomalies, sensorineural hearing loss, and ectodermal dysplasia-like phenotypes who have heterozygous de novo variants in this specific region of the gene. …

The Relationship Of Health Literacy To Health Outcomes Among Individuals With Traumatic Brain Injury: A Traumatic Brain Injury Model Systems Study, Monique R Pappadis, Angelle M Sander, Shannon B Juengst, Luis Leon-Novelo, Esther Ngan, Kathleen R Bell, John D Corrigan, Simon Driver, Laura E Dreer, Anthony H Lequerica

Faculty, Staff and Student Publications

OBJECTIVE: To examine the associations between health literacy and health outcomes among individuals with traumatic brain injury (TBI) at least a year post-injury.

SETTING: Community following discharge from inpatient rehabilitation.

PARTICIPANTS: A total of 205 individuals with complicated mild to severe TBI who completed a TBI Model Systems National Database follow-up interview and a web-based health literacy measure.

DESIGN: A multicenter, cross-sectional, observational study.

MAIN MEASURES: The Health Literacy Assessment Using Talking Touchscreen Technology (Health LiTT), number of comorbid conditions (Medical and Mental Health Comorbidities Interview [MMHCI]), perceived physical and mental health (PROMIS Global Physical and Mental Health subscales), Patient …

Association Of Timely Comprehensive Genomic Profiling With Precision Oncology Treatment Use And Patient Outcomes In Advanced Non-Small-Cell Lung Cancer, Jeff Yorio, Katherine T Lofgren, Jessica K Lee, Khaled Tolba, Geoffrey R Oxnard, Alexa B Schrock, Richard S P Huang, Lorraine Brisbin

Faculty, Staff and Student Publications

PURPOSE: Timely biomarker testing remains out of reach for many patients with advanced non-small-cell lung cancer (aNSCLC). Here, we studied the quality-of-care implications of closing the gap in timely receipt of comprehensive genomic profiling (CGP) to inform first-line (1L) decisions.

METHODS: Using a real-world clinicogenomic database, we studied testing and 1L treatment patterns in aNSCLC after the approval of pembrolizumab in combination with pemetrexed and carboplatin (May 10, 2017). To estimate the association of timely CGP results with therapy selection and patient outcomes, we identified patients with no previous genomic testing beyond PD-L1 immunohistochemistry and dichotomized patients by whether CGP …

A Clinical Practice Guideline For The Management Of Patients With Acute Spinal Cord Injury: Recommendations On Hemodynamic Management, Brian K Kwon, Lindsay A Tetreault, Allan R Martin, Paul M Arnold, Rex A W Marco, Virginia F J Newcombe, Carl M Zipser, Stephen L Mckenna, Radha Korupolu, Chris J Neal, Rajiv Saigal, Nina E Glass, Sam Douglas, Mario Ganau, Vafa Rahimi-Movaghar, James S Harrop, Bizhan Aarabi, Jefferson R Wilson, Nathan Evaniew, Andrea C Skelly, Michael G Fehlings

Faculty, Staff and Student Publications

STUDY DESIGN: Clinical practice guideline development following the GRADE process.

OBJECTIVES: Hemodynamic management is one of the only available treatment options that likely improves neurologic outcomes in patients with acute traumatic spinal cord injury (SCI). Augmenting mean arterial pressure (MAP) aims to improve blood perfusion and oxygen delivery to the injured spinal cord in order to minimize secondary ischemic damage to neural tissue. The objective of this guideline was to update the 2013 AANS/CNS recommendations on the hemodynamic management of patients with acute traumatic SCI, acknowledging that much has been published in this area since its publication. Specifically, we sought …

Interventions To Optimize Spinal Cord Perfusion In Patients With Acute Traumatic Spinal Cord Injury: An Updated Systematic Review, Nathan Evaniew, Benjamin Davies, Farzin Farahbakhsh, Michael G Fehlings, Mario Ganau, Daniel Graves, James D Guest, Radha Korupolu, Allan R Martin, Stephen L Mckenna, Lindsay A Tetreault, Aditya Vedantam, Erika D Brodt, Andrea C Skelly, Brian K Kwon

Faculty, Staff and Student Publications

STUDY DESIGN: Systematic review update.

OBJECTIVES: Interventions that aim to optimize spinal cord perfusion are thought to play an important role in minimizing secondary ischemic damage and improving outcomes in patients with acute traumatic spinal cord injuries (SCIs). However, exactly how to optimize spinal cord perfusion and enhance neurologic recovery remains controversial. We performed an update of a recent systematic review (Evaniew et al, J. Neurotrauma 2020) to evaluate the effects of Mean Arterial Pressure (MAP) support or Spinal Cord Perfusion Pressure (SCPP) support on neurological recovery and rates of adverse events among patients with acute traumatic SCI.

METHODS: We …

Quantification And Visualization Of Cis-Regulatory Dynamics In Single-Cell Multi-Omics Data With Treasmo, Chaozhong Liu, Linhua Wang, Zhandong Liu

Faculty, Staff and Students Publications

Recent advances in single-cell multi-omics technologies have provided unprecedented insights into regulatory processes. We introduce TREASMO, a versatile Python package designed to quantify and visualize transcriptional regulatory dynamics in single-cell multi-omics datasets. TREASMO has four modules, spanning data preparation, correlation quantification, downstream analysis and visualization, enabling comprehensive dataset exploration. By introducing a novel single-cell gene-peak correlation strength index, TREASMO facilitates accurate identification of regulatory changes at single-cell resolution. Validation on a hematopoietic stem and progenitor cell dataset showcases TREASMO's capacity in quantifying the gene-peak correlation strength at the single-cell level, identifying regulatory markers and discovering temporal regulatory patterns along the …

Polyaminer-Bulk Is A Deep Learning-Based Algorithm That Decodes Alternative Polyadenylation Dynamics From Bulk Rna-Seq Data, Venkata Soumith Jonnakuti, Eric J Wagner, Mirjana Maletić-Savatić, Zhandong Liu, Hari Krishna Yalamanchili

Faculty, Staff and Students Publications

Alternative polyadenylation (APA) is a key post-transcriptional regulatory mechanism; yet, its regulation and impact on human diseases remain understudied. Existing bulk RNA sequencing (RNA-seq)-based APA methods predominantly rely on predefined annotations, severely impacting their ability to decode novel tissue- and disease-specific APA changes. Furthermore, they only account for the most proximal and distal cleavage and polyadenylation sites (C/PASs). Deconvoluting overlapping C/PASs and the inherent noisy 3' UTR coverage in bulk RNA-seq data pose additional challenges. To overcome these limitations, we introduce PolyAMiner-Bulk, an attention-based deep learning algorithm that accurately recapitulates C/PAS sequence grammar, resolves overlapping C/PASs, captures non-proximal-to-distal APA changes, …

Factors Affecting Selection Of Trainee For Neurointervention (Fasten), Mohamed Elfil, Rami Z Morsi, Sherief Ghozy, Ahmed Elmashad, Adnan Siddiqui, Alhamza R Al-Bayati, Ali Alaraj, Allan Brook, Anthony W Kam, Arindam Rano Chatterjee, Athos Patsalides, Ben Waldau, Charles J Prestigiacomo, Charles Matouk, Clemens M Schirmer, David Altschul, David T Parrella, Gabor Toth, Gaurav Jindal, Hamza A Shaikh, Jaydevsinh N Dolia, Johanna T Fifi, Justin F Fraser, Justin Thomas Do, Krishna Amuluru, Louis J Kim, Mark Harrigan, Matthew R Amans, Max Kole, Max Mokin, Michael Abraham, Mouhammad Jumaa, Nazli Janjua, Osama Zaidat, Patrick P Youssef, Priyank Khandelwal, Qingliang Tony Wang, Ramesh Grandhi, Ricardo Hanel, Ryan T Kellogg, Santiago Ortega-Gutierrez, Sunil Sheth, Thanh N Nguyen, Viktor Szeder, Yin C Hu, Albert J Yoo, Omar Tanweer, Brian Jankowitz, Jeremy J Heit, Richard Williamson, Tareq Kass-Hout, Richard W Crowley, Mohammad El-Ghanem, Fawaz Al-Mufti

Faculty, Staff and Students Publications

BACKGROUND AND IMPORTANCE: Neurointervention is a very competitive specialty in the United States due to the limited number of training spots and the larger pool of applicants. The training standards are continuously updated to ensure solid training experiences. Factors affecting candidate(s) selection have not been fully established yet. Our study aims to investigate the factors influencing the selection process.

METHODS: A 52-question survey was distributed to 93 program directors (PDs). The survey consisted of six categories: (a) Program characteristics, (b) Candidate demographics, (c) Educational credentials, (d) Personal traits, (e) Research and extracurricular activities, and (f) Overall final set of characteristics. …

The Effects Of Covid-19 Mrna Vaccine On Adolescence Gynecological Well-Being, Shih-Chiao Tseng, Dana Cherry, Mansoo Ko, Steven R Fisher, Michael Furtado, Shuo-Hsiu Chang

Faculty, Staff and Student Publications

PURPOSE: Evidence suggests that transcranial direct current stimulation (tDCS) can enhance motor performance and learning of hand tasks in persons with chronic stroke (PCS). However, the effects of tDCS on the locomotor tasks in PCS are unclear. This pilot study aimed to: (1) determine aggregate effects of anodal tDCS combined with step training on improvements of the neural and biomechanical attributes of stepping initiation in a small cohort of persons with chronic stroke (PCS) over a 4-week training program; and (2) assess the feasibility and efficacy of this novel approach for improving voluntary stepping initiation in PCS.

METHODS: A total …

Progestin-Associated Meningiomatosis With Unusual Schwannoma-Like Morphology, Katherine A Krause, Jared K Woods, Alexandra J Golby, Eudocia Q Lee, Shyam Tanguturi, Zachary Spigelman, Azra H Ligon, Umberto De Girolami, Matthew Torre

Duncan NRI Faculty and Staff Publications

No abstract provided.

Uchl1 Is A Potential Molecular Indicator And Therapeutic Target For Neuroendocrine Carcinomas, Shiqin Liu, Timothy Chai, Fernando Garcia-Marques, Qingqing Yin, En-Chi Hsu, Michelle Shen, Angus Martin Shaw Toland, Abel Bermudez, Alifiani B Hartono, Christopher F Massey, Chung S Lee, Liwei Zheng, Maya Baron, Caden J Denning, Merve Aslan, Holly M Nguyen, Rosalie Nolley, Amina Zoubeidi, Millie Das, Christian A Kunder, Brooke E Howitt, H Tom Soh, Irving L Weissman, Michael A Liss, Arnold I Chin, James D Brooks, Eva Corey, Sharon J Pitteri, Jiaoti Huang, Tanya Stoyanova

Faculty, Staff and Student Publications

Neuroendocrine carcinomas, such as neuroendocrine prostate cancer and small-cell lung cancer, commonly have a poor prognosis and limited therapeutic options. We report that ubiquitin carboxy-terminal hydrolase L1 (UCHL1), a deubiquitinating enzyme, is elevated in tissues and plasma from patients with neuroendocrine carcinomas. Loss of UCHL1 decreases tumor growth and inhibits metastasis of these malignancies. UCHL1 maintains neuroendocrine differentiation and promotes cancer progression by regulating nucleoporin, POM121, and p53. UCHL1 binds, deubiquitinates, and stabilizes POM121 to regulate POM121-associated nuclear transport of E2F1 and c-MYC. Treatment with the UCHL1 inhibitor LDN-57444 slows tumor growth and metastasis across neuroendocrine carcinomas. The combination of …

Cpsf3 Inhibition Blocks Pancreatic Cancer Cell Proliferation Through Disruption Of Core Histone Mrna Processing, Abdulrahman A Alahmari, Aditi H Chaubey, Venkata S Jonnakuti, Arwen A Tisdale, Carla D Schwarz, Abigail C Cornwell, Kathryn E Maraszek, Emily J Paterson, Minsuh Kim, Swati Venkat, Eduardo Cortes Gomez, Jianmin Wang, Katerina V Gurova, Hari Krishna Yalamanchili, Michael E Feigin

Duncan NRI Faculty and Staff Publications

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited effective treatment options, potentiating the importance of uncovering novel drug targets. Here, we target cleavage and polyadenylation specificity factor 3 (CPSF3), the 3′ endonuclease that catalyzes mRNA cleavage during polyadenylation and histone mRNA processing. We find that CPSF3 is highly expressed in PDAC and is associated with poor prognosis. CPSF3 knockdown blocks PDAC cell proliferation and colony formation in vitro and tumor growth in vivo. Chemical inhibition of CPSF3 by the small molecule JTE-607 also attenuates PDAC cell proliferation and colony formation, while it has no effect on cell proliferation …

Cpsf3 Inhibition Blocks Pancreatic Cancer Cell Proliferation Through Disruption Of Core Histone Mrna Processing, Abdulrahman A Alahmari, Aditi H Chaubey, Venkata S Jonnakuti, Arwen A Tisdale, Carla D Schwarz, Abigail C Cornwell, Kathryn E Maraszek, Emily J Paterson, Minsuh Kim, Swati Venkat, Eduardo Cortes Gomez, Jianmin Wang, Katerina V Gurova, Hari Krishna Yalamanchili, Michael E Feigin

Faculty, Staff and Students Publications

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with limited effective treatment options, potentiating the importance of uncovering novel drug targets. Here, we target cleavage and polyadenylation specificity factor 3 (CPSF3), the 3′ endonuclease that catalyzes mRNA cleavage during polyadenylation and histone mRNA processing. We find that CPSF3 is highly expressed in PDAC and is associated with poor prognosis. CPSF3 knockdown blocks PDAC cell proliferation and colony formation in vitro and tumor growth in vivo. Chemical inhibition of CPSF3 by the small molecule JTE-607 also attenuates PDAC cell proliferation and colony formation, while it has no effect on cell proliferation …

Development And Validation Of Parent-Reported Gastrointestinal Health Scale In Mecp2 Duplication Syndrome, Davut Pehlivan, Sukru Aras, Daniel G Glaze, Muharrem Ak, Bernhard Suter, Kathleen J Motil

Faculty, Staff and Students Publications

BACKGROUND/AIMS: We aimed to develop a validated patient-reported Gastrointestinal Health Scale (GHS) specific to MECP2 Duplication Syndrome (MDS) to be used in clinical trials.

METHODS: MDS parents completed a Gastrointestinal Health Questionnaire (GHQ) to investigate the most relevant and important items associated with gastrointestinal problems in MECP2-related disorders. Item reduction was executed according to EORTC guidelines. We performed reliability and validity studies for the finalized scale.

RESULTS: A total of 106 surveys were eligible for item reduction and validation processes. The initial 55 items were reduced to 38 items based on parent responses, expert opinion, and initial confirmatory factor analysis …

Longitudinal Single-Cell Transcriptional Dynamics Throughout Neurodegeneration In Sca1, Leon Tejwani, Neal G Ravindra, Changwoo Lee, Yubao Cheng, Billy Nguyen, Kimberly Luttik, Luhan Ni, Shupei Zhang, Logan M Morrison, John Gionco, Yangfei Xiang, Jennifer Yoon, Hannah Ro, Fatema Haidery, Rosalie M Grijalva, Eunwoo Bae, Kristen Kim, Regina T Martuscello, Harry T Orr, Huda Y Zoghbi, Hayley S Mcloughlin, Laura P W Ranum, Vikram G Shakkottai, Phyllis L Faust, Siyuan Wang, David Van Dijk, Janghoo Lim

Duncan NRI Faculty and Staff Publications

Neurodegeneration is a protracted process involving progressive changes in myriad cell types that ultimately results in the death of vulnerable neuronal populations. To dissect how individual cell types within a heterogeneous tissue contribute to the pathogenesis and progression of a neurodegenerative disorder, we performed longitudinal single-nucleus RNA sequencing of mouse and human spinocerebellar ataxia type 1 (SCA1) cerebellar tissue, establishing continuous dynamic trajectories of each cell population. Importantly, we defined the precise transcriptional changes that precede loss of Purkinje cells and, for the first time, identified robust early transcriptional dysregulation in unipolar brush cells and oligodendroglia. Finally, we applied a …

Parenting Influences On Frontal Lobe Gray Matter And Preterm Toddlers' Problem-Solving Skills, Josselyn S Muñoz, Megan E Giles, Kelly A Vaughn, Ying Wang, Susan H Landry, Johanna R Bick, Dana M Demaster

Faculty, Staff and Student Publications

Children born preterm often face challenges with self-regulation during toddlerhood. This study examined the relationship between prematurity, supportive parent behaviors, frontal lobe gray matter volume (GMV), and emotion regulation (ER) among toddlers during a parent-assisted, increasingly complex problem-solving task, validated for this age range. Data were collected from preterm toddlers (n = 57) ages 15–30 months corrected for prematurity and their primary caregivers. MRI data were collected during toddlers’ natural sleep. The sample contained three gestational groups: 22–27 weeks (extremely preterm; EPT), 28–33 weeks (very preterm; VPT), and 34–36 weeks (late preterm; LPT). Older toddlers became more compliant as …

Insights Of Clinical Significance From 109 695 Solid Tumor Tissue-Based Comprehensive Genomic Profiles, Andreas M Heilmann, Jonathan W Riess, Margaret Mclaughlin-Drubin, Richard S P Huang, Meghann Hjulstrom, James Creeden, Brian M Alexander, Rachel L Erlich

Faculty, Staff and Student Publications

BACKGROUND: FoundationOneCDx is approved in the US and Japan as a companion diagnostic test to identify patients with cancer who may benefit from treatment with 30 drug therapies in the US and 23 in Japan. Tumor profiling with FoundationOneCDx also detects genomic findings with evidence of clinical significance that may inform clinical care decisions beyond companion diagnostic claims. This observational study reports the breadth and impact of clinical decision insights from FoundationOneCDx solid tumor profiles.

MATERIALS AND METHODS: Consecutive test result reports for patients with solid tumor diagnoses (n = 109 695) were retrospectively analyzed for clinically significant predictive, prognostic, …

Sarin-Induced Neuroinflammation In Mouse Brain Is Attenuated By The Caspase Inhibitor Q-Vd-Oph, Ekta J. Shah, William C. Grunwald Jr., Teresa L. Garrett, Thomas L. Brown, David R. Cool

Neuroscience, Cell Biology & Physiology Faculty Publications

Organophosphates cause hyperstimulation of the central nervous system, leading to extended seizures, convulsions, and brain damage. Sarin is a highly toxic organophosphate nerve agent that has been employed in several terrorist attacks. The prolonged toxicity of sarin may be enhanced by the neuroinflammatory response initiated by the inflammasome, caspase involvement, and generation/release of proinflammatory cytokines. Since neurodegeneration and neuroinflammation are prevalent in sarin-exposed animals, we were interested in evaluating the capacity of quinolyl-valyl-O-methylaspartyl-[-2,6-difluorophenoxy]-methyl ketone (Q-VD-OPh), a pan caspase inhibitor to attenuate neuroinflammation following sarin exposure. To test this hypothesis, sarin-exposed C57BL/6 mice were treated with Q-VD-OPh or negative control quinolyl-valyl-O-methylglutamyl-[-2,6-difluorophenoxy]-methyl …

Neurologic Morbidity And Functional Independence In Adult Survivors Of Childhood Cancer, Stefanie C Vuotto, Mingjuan Wang, M Fatih Okcu, Daniel C Bowers, Nicole J Ullrich, Kirsten K Ness, Chenghong Li, Deo Kumar Srivastava, Rebecca M Howell, Todd M Gibson, Wendy M Leisenring, Kevin C Oeffinger, Leslie L Robison, Gregory T Armstrong, Kevin R Krull, Tara M Brinkman

Faculty, Staff and Student Publications

OBJECTIVE: To examine associations between neurologic late effects and attainment of independence in adult survivors of childhood cancer treated with central nervous system (CNS)-directed therapies.

METHODS: A total of 7881 survivors treated with cranial radiation therapy (n = 4051; CRT) and/or intrathecal methotrexate (n = 4193; IT MTX) ([CNS-treated]; median age [range] = 25.5 years [18-48]; time since diagnosis = 17.7 years [6.8-30.2]) and 8039 without CNS-directed therapy reported neurologic conditions including stroke, seizure, neurosensory deficits, focal neurologic dysfunction, and migraines/severe headaches. Functional independence was assessed using latent class analysis with multiple indicators (independent living, assistance with routine and personal …

The Ddhd2-Stxbp1 Interaction Mediates Long-Term Memory Via Generation Of Saturated Free Fatty Acids, Isaac O Akefe, Saber H Saber, Benjamin Matthews, Bharat G Venkatesh, Rachel S Gormal, Daniel G Blackmore, Suzy Alexander, Emma Sieriecki, Yann Gambin, Jesus Bertran-Gonzalez, Nicolas Vitale, Yann Humeau, Arnaud Gaudin, Sevannah A Ellis, Alysee A Michaels, Mingshan Xue, Benjamin Cravatt, Merja Joensuu, Tristan P Wallis, Frédéric A Meunier

Faculty, Staff and Students Publications

The phospholipid and free fatty acid (FFA) composition of neuronal membranes plays a crucial role in learning and memory, but the mechanisms through which neuronal activity affects the brain's lipid landscape remain largely unexplored. The levels of saturated FFAs, particularly of myristic acid (C14:0), strongly increase during neuronal stimulation and memory acquisition, suggesting the involvement of phospholipase A1 (PLA1) activity in synaptic plasticity. Here, we show that genetic ablation of the PLA1 isoform DDHD2 in mice dramatically reduces saturated FFA responses to memory acquisition across the brain. Furthermore, DDHD2 loss also decreases memory performance in reward-based learning and spatial memory …