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Vikas Daggubati, Akshara Vykunta, Abrar Choudhury, Zulekha Qadeer, Kanish Mirchia, Olivier Saulnier, Naomi Zakimi, Kelly Hines, Michael Paul, Linyu Wang, Natalia Jura, Libin Xu, Jeremy Reiter, Michael Taylor, William Weiss, David Raleigh
Hedgehog (Hh) signaling is essential for development, homeostasis, and regeneration 1 . Misactivation of the Hh pathway underlies medulloblastoma, the most common malignant brain tumor in children, and basal cell carcinoma (BCC), the most common cancer in the United States 2 . Primary cilia regulate Hh signal transduction 3 , but target genes that drive cell fate decisions in response to ciliary ligands or oncogenic Hh signaling are incompletely understood. Here we define the Hh gene expression program using RNA sequencing of cultured cells treated with ciliary ligands, BCCs from humans, and Hh-associated medulloblastomas from humans and mice (Fig...
August 3, 2023: Research Square
#22
David Raleigh, Kanish Mirchia, Abrar Choudhury, Tara Joseph, Janeth Birrueta, Joanna Phillips, Aparna Bhaduri, Elizabeth Crouch, Arie Perry
Meningeal solitary fibrous tumors (SFTs) are rare mesenchymal neoplasms that are associated with hematogenous metastasis, and the cell states and spatial transcriptomic architecture of SFTs are unknown. Here we use single-cell and spatial RNA sequencing to show SFTs are comprised of regionally distinct gene expression programs that resemble cerebral vascular development and homeostasis. Our results shed light on pathways underlying SFT biology in comparison to other central nervous system tumors and provide a framework for integrating single-cell and spatial transcriptomic data from human cancers and normal tissues...
July 26, 2023: Research Square
#23
Abrar Choudhury, Martha A Cady, Calixto-Hope G Lucas, Hinda Najem, Joanna J Phillips, Brisa Palikuqi, Naomi Zakimi, Tara Joseph, Janeth Ochoa Birrueta, William C Chen, Nancy Ann Oberheim Bush, Shawn L Hervey-Jumper, Ophir D Klein, Christine M Toedebusch, Craig M Horbinski, Stephen T Magill, Aparna Bhaduri, Arie Perry, Peter J Dickinson, Amy B Heimberger, Alan Ashworth, Elizabeth E Crouch, David R Raleigh
Meningiomas are the most common primary intracranial tumors 1-3 . Treatments for patients with meningiomas are limited to surgery and radiotherapy, and systemic therapies remain ineffective or experimental 4,5 . Resistance to radiotherapy is common in high-grade meningiomas 6 , and the cell types and signaling mechanisms driving meningioma tumorigenesis or resistance to radiotherapy are incompletely understood. Here we report NOTCH3 drives meningioma tumorigenesis and resistance to radiotherapy and find NOTCH3+ meningioma mural cells are conserved across meningiomas from humans, dogs, and mice...
July 11, 2023: bioRxiv
#24
REVIEW
Khizar R Nandoliya, Nishanth S Sadagopan, Vineeth Thirunavu, Ethan J Houskamp, Constantine L Karras, Rahul K Chaliparambil, Nikhil Sriram, Pouya Jamshidi, David R Raleigh, Rimas V Lukas, Stephen T Magill
Most of the literature on pineoblastoma consists of case reports and single-institution series. The goal of this systematic review and individual patient data (IPD) analysis was to summarize the existing literature, identify factors associated with overall survival (OS), and provide a contemporary update on prognosis for patients with pineoblastoma. Forty-four studies were identified with 298 patients having IPD. Kaplan-Meier analyses were used to report survival outcomes based on age, tumor metastases, extent of resection (EOR), adjuvant therapy, and publication year...
June 27, 2023: Cancers
#25
REVIEW
Matthew S Susko, David R Raleigh
Meningiomas are the most common primary intracranial brain tumor, and have a heterogeneous biology and an unmet need for targeted treatment options. Existing treatments for meningiomas are limited to surgery, radiotherapy, or a combination of these depending on clinical and histopathological features. Treatment recommendations for meningioma patients take into consideration radiologic features, tumor size and location, and medical comorbidities, all of which may influence the ability to undergo complete resection...
2023: Advances in Experimental Medicine and Biology
#26
Calixto-Hope Lucas, Kanish Mirchia, Kyounghee Seo, Hinda Najem, William Chen, Naomi Zakimi, Abrar Choudhury, S John Liu, Joanna Phillips, Stephen Magill, Craig Horbinski, David Solomon, Arie Perry, Harish Vasudevan, Amy Heimberger, David Raleigh
Intratumor heterogeneity underlies cancer evolution and treatment resistance 1-5 , but targetable mechanisms driving intratumor heterogeneity are poorly understood. Meningiomas are the most common primary intracranial tumors and are resistant to all current medical therapies 6,7 . High-grade meningiomas cause significant neurological morbidity and mortality and are distinguished from low-grade meningiomas by increased intratumor heterogeneity arising from clonal evolution and divergence 8 . Here we integrate spatial transcriptomic and spatial protein profiling approaches across high-grade meningiomas to identify genomic, biochemical, and cellular mechanisms linking intratumor heterogeneity to the molecular, temporal, and spatial evolution of cancer...
May 15, 2023: Research Square
#27
Justin Z Wang, Vikas Patil, Jeff Liu, Helin Dogan, Ghazaleh Tabatabai, Leeor S Yefet, Felix Behling, Elgin Hoffman, Severa Bunda, Rebecca Yakubov, Ramneet Kaloti, Sebastian Brandner, Andrew Gao, Aaron Cohen-Gadol, Jill Barnholtz-Sloan, Marco Skardelly, Marcos Tatagiba, David R Raleigh, Felix Sahm, Paul C Boutros, Kenneth Aldape, Farshad Nassiri, Gelareh Zadeh
No abstract text is available yet for this article.
May 12, 2023: Acta Neuropathologica
#28
JOURNAL ARTICLE
Saritha Krishna, Abrar Choudhury, Michael B Keough, Kyounghee Seo, Lijun Ni, Sofia Kakaizada, Anthony Lee, Alexander Aabedi, Galina Popova, Benjamin Lipkin, Caroline Cao, Cesar Nava Gonzales, Rasika Sudharshan, Andrew Egladyous, Nyle Almeida, Yalan Zhang, Annette M Molinaro, Humsa S Venkatesh, Andy G S Daniel, Kiarash Shamardani, Jeanette Hyer, Edward F Chang, Anne Findlay, Joanna J Phillips, Srikantan Nagarajan, David R Raleigh, David Brang, Michelle Monje, Shawn L Hervey-Jumper
Gliomas synaptically integrate into neural circuits1,2 . Previous research has demonstrated bidirectional interactions between neurons and glioma cells, with neuronal activity driving glioma growth1-4 and gliomas increasing neuronal excitability2,5-8 . Here we sought to determine how glioma-induced neuronal changes influence neural circuits underlying cognition and whether these interactions influence patient survival. Using intracranial brain recordings during lexical retrieval language tasks in awake humans together with site-specific tumour tissue biopsies and cell biology experiments, we find that gliomas remodel functional neural circuitry such that task-relevant neural responses activate tumour-infiltrated cortex well beyond the cortical regions that are normally recruited in the healthy brain...
May 3, 2023: Nature
#29
JOURNAL ARTICLE
Increased mRNA expression of CDKN2A is a transcriptomic marker of clinically aggressive meningiomas.
Justin Z Wang, Vikas Patil, Jeff Liu, Helin Dogan, Ghazaleh Tabatabai, Leeor S Yefet, Felix Behling, Elgin Hoffman, Severa Bunda, Rebecca Yakubov, Ramneet Kaloti, Sebastian Brandner, Andrew Gao, Aaron Cohen-Gadol, Jill Barnholtz-Sloan, Marco Skardelly, Marcos Tatagiba, David R Raleigh, Felix Sahm, Paul C Boutros, Kenneth Aldape, Farshad Nassiri, Gelareh Zadeh
Homozygous deletion of CDKN2A/B was recently incorporated into the World Health Organization classification for grade 3 meningiomas. While this marker is overall rare in meningiomas, its relationship to other CDKN2A alterations on a transcriptomic, epigenomic, and copy number level has not yet been determined. We therefore utilized multidimensional molecular data of 1577 meningioma samples from 6 independent cohorts enriched for clinically aggressive meningiomas to comprehensively interrogate the spectrum of CDKN2A alterations through DNA methylation, copy number variation, transcriptomics, and proteomics using an integrated molecular approach...
July 2023: Acta Neuropathologica
#30
David Raleigh, William Chen, Abrar Choudhury, Mark Youngblood, Mei-Yin Polley, Calixto-Hope Lucas, Kanish Mirchia, Sybren Maas, Abigail Suwala, Minhee Won, James Bayley, Akdes Harmanci, Arif Harmanci, Tiemo Klisch, Minh Nguyen, Harish Vasudevan, Kathleen McCortney, Theresa Yu, Varun Bhave, Tai-Chung Lam, Jenny Pu, Gilberto Leung, Jason Chang, Haley Perlow, Joshua Palmer, Christine Haberler, Anna Berghoff, Matthias Preusser, Theodore Nicolaides, Christian Mawrin, Sameer Agnihotri, Adam Resnick, Brian Rood, Jessica Chew, Jacob Young, Lauren Boreta, Steve Braunstein, Jessica Schulte, Nicholas Butowski, Sandro Santagata, David Spetzler, Nancy Ann Oberheim Bush, Javier Villanueva-Meyer, James Chandler, David Solomon, C Rogers, Stephanie Pugh, Minesh Mehta, Penny Sneed, Mitchel Berger, Craig Horbinski, Michael McDermott, Arie Perry, Wenya Bi, Akash Patel, Felix Sahm, Stephen Magill
Background Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and current indications for postoperative radiotherapy are controversial. Recent studies have proposed prognostic meningioma classification systems using DNA methylation profiling, copy number variants, DNA sequencing, RNA sequencing, histology, or integrated models based on multiple combined features. Targeted gene expression profiling has generated robust biomarkers integrating multiple molecular features for other cancers, but is understudied for meningiomas...
March 20, 2023: Research Square
#31
MerlinS13 phosphorylation controls meningioma Wnt signaling and magnetic resonance imaging features.
Charlotte Eaton, Lauro Avalos, S John Liu, Tim Casey-Clyde, Paola Bisignano, Calixto-Hope Lucas, Erica Stevenson, Abrar Choudhury, Harish Vasudevan, Stephen Magill, Nevan Krogan, Javier Villanueva-Meyer, Danielle Swaney, David Raleigh
Meningiomas are the most common primary intracranial tumors and are associated with inactivation of the tumor suppressor NF2 /Merlin, but one-third of meningiomas retain Merlin expression and typically have favorable clinical outcomes. Biochemical mechanisms underlying Merlin-intact meningioma growth are incompletely understood, and non-invasive biomarkers that predict meningioma outcomes and could be used to guide treatment de-escalation or imaging surveillance of Merlin-intact meningiomas are lacking. Here we integrate single-cell RNA sequencing, proximity-labeling proteomic mass spectrometry, mechanistic and functional approaches, and magnetic resonance imaging (MRI) across meningioma cells, xenografts, and human patients to define biochemical mechanisms and an imaging biomarker that distinguish Merlin-intact meningiomas with favorable clinical outcomes from meningiomas with unfavorable clinical outcomes...
March 14, 2023: Research Square
#32
JOURNAL ARTICLE
A Basit Khan, Collin W English, William C Chen, Prazwal Athukuri, James C Bayley, Vicky L Brandt, Arya Shetty, Caroline C Hadley, Abrar Choudhury, Hsiang-Chih Lu, Arif O Harmanci, Akdes S Harmanci, Stephen T Magill, David R Raleigh, Tiemo J Klisch, Akash J Patel
No abstract text is available yet for this article.
February 2, 2023: Acta Neuropathologica
#33
LETTER
Loss of p16 expression is a sensitive marker of CDKN2A homozygous deletion in malignant meningiomas.
Vivian Tang, Rufei Lu, Kanish Mirchia, Jessica Van Ziffle, Patrick Devine, Julieann Lee, Joanna J Phillips, Arie Perry, David R Raleigh, Calixto-Hope G Lucas, David A Solomon
No abstract text is available yet for this article.
April 2023: Acta Neuropathologica
#34
JOURNAL ARTICLE
Lin Wang, Jangham Jung, Husam Babikir, Karin Shamardani, Saket Jain, Xi Feng, Nalin Gupta, Susanna Rosi, Susan Chang, David Raleigh, David Solomon, Joanna J Phillips, Aaron A Diaz
Recent longitudinal studies of glioblastoma (GBM) have demonstrated a lack of apparent selection pressure for specific DNA mutations in recurrent disease. Single-cell lineage tracing has shown that GBM cells possess a high degree of plasticity. Together this suggests that phenotype switching, as opposed to genetic evolution, may be the escape mechanism that explains the failure of precision therapies to date. We profiled 86 primary-recurrent patient-matched paired GBM specimens with single-nucleus RNA, single-cell open-chromatin, DNA and spatial transcriptomic/proteomic assays...
December 2022: Nature Cancer
#35
JOURNAL ARTICLE
Harish N Vasudevan, Matthew S Susko, Lijun Ma, Jean L Nakamura, David R Raleigh, Lauren Boreta, Shannon Fogh, Philip V Theodosopoulos, Michael W McDermott, Katy K Tsai, Penny K Sneed, Steve E Braunstein
No abstract text is available yet for this article.
November 15, 2022: World Neurosurgery
#36
JOURNAL ARTICLE
Derrick Lee, Ryan C Gimple, Xujia Wu, Briana C Prager, Zhixin Qiu, Qiulian Wu, Vikas Daggubati, Aruljothi Mariappan, Jay Gopalakrishnan, Matthew R Sarkisian, David R Raleigh, Jeremy N Rich
Glioblastoma ranks among the most aggressive and lethal of all human cancers. Self-renewing, highly tumorigenic glioblastoma stem cells (GSCs) contribute to therapeutic resistance and maintain cellular heterogeneity. Here, we interrogated superenhancer landscapes of primary glioblastoma specimens and patient-derived GSCs, revealing a kelch domain-containing gene (KLHDC8A) with a previously unknown function as an epigenetically-driven oncogene. Targeting KLHDC8A decreased GSC proliferation and self-renewal, induced apoptosis, and impaired in vivo tumor growth...
November 17, 2022: Journal of Clinical Investigation
#37
JOURNAL ARTICLE
Minh P Nguyen, Kyounghee Seo, Charlotte D Eaton, Calixto-Hope G Lucas, William C Chen, Abrar Choudhury, Jacob S Young, David R Raleigh
No abstract text is available yet for this article.
January 2022: Neuro-oncology advances
#38
JOURNAL ARTICLE
Nadine Kotlarz, David A Holcomb, A B M Tanvir Pasha, Stacie Reckling, Judith Kays, Yi-Chun Lai, Sean Daly, Sivaranjani Palani, Erika Bailey, Virginia T Guidry, Ariel Christensen, Steven Berkowitz, Jane A Hoppin, Helena Mitasova, Lawrence S Engel, Francis L de Los Reyes, Angela Harris
Objectives. To compare 4 COVID-19 surveillance metrics in a major metropolitan area. Methods. We analyzed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA in wastewater influent and primary solids in Raleigh, North Carolina, from April 10 through December 13, 2020. We compared wastewater results with lab-confirmed COVID-19 cases and syndromic COVID-like illness (CLI) cases to answer 3 questions: (1) Did they correlate? (2) What was the temporal alignment of the different surveillance systems? (3) Did periods of significant change (i...
November 10, 2022: American Journal of Public Health
#39
JOURNAL ARTICLE
Jacqueline Oehri, Gabriela Schaepman-Strub, Jin-Soo Kim, Raleigh Grysko, Heather Kropp, Inge Grünberg, Vitalii Zemlianskii, Oliver Sonnentag, Eugénie S Euskirchen, Merin Reji Chacko, Giovanni Muscari, Peter D Blanken, Joshua F Dean, Alcide di Sarra, Richard J Harding, Ireneusz Sobota, Lars Kutzbach, Elena Plekhanova, Aku Riihelä, Julia Boike, Nathaniel B Miller, Jason Beringer, Efrén López-Blanco, Paul C Stoy, Ryan C Sullivan, Marek Kejna, Frans-Jan W Parmentier, John A Gamon, Mikhail Mastepanov, Christian Wille, Marcin Jackowicz-Korczynski, Dirk N Karger, William L Quinton, Jaakko Putkonen, Dirk van As, Torben R Christensen, Maria Z Hakuba, Robert S Stone, Stefan Metzger, Baptiste Vandecrux, Gerald V Frost, Martin Wild, Birger Hansen, Daniela Meloni, Florent Domine, Mariska Te Beest, Torsten Sachs, Aram Kalhori, Adrian V Rocha, Scott N Williamson, Sara Morris, Adam L Atchley, Richard Essery, Benjamin R K Runkle, David Holl, Laura D Riihimaki, Hiroki Iwata, Edward A G Schuur, Christopher J Cox, Andrey A Grachev, Joseph P McFadden, Robert S Fausto, Mathias Göckede, Masahito Ueyama, Norbert Pirk, Gijs de Boer, M Syndonia Bret-Harte, Matti Leppäranta, Konrad Steffen, Thomas Friborg, Atsumu Ohmura, Colin W Edgar, Johan Olofsson, Scott D Chambers
Despite the importance of high-latitude surface energy budgets (SEBs) for land-climate interactions in the rapidly changing Arctic, uncertainties in their prediction persist. Here, we harmonize SEB observations across a network of vegetated and glaciated sites at circumpolar scale (1994-2021). Our variance-partitioning analysis identifies vegetation type as an important predictor for SEB-components during Arctic summer (June-August), compared to other SEB-drivers including climate, latitude and permafrost characteristics...
October 31, 2022: Nature Communications
#40
REVIEW
William C Chen, Haley K Perlow, Abrar Choudhury, Minh P Nguyen, Kanish Mirchia, Mark W Youngblood, Calixto-Hope G Lucas, Joshua D Palmer, Stephen T Magill, David R Raleigh
Meningiomas are the most common primary central nervous system neoplasm. Despite promising recent progress in elucidating the genomic landscape and underlying biology of these histologically, molecularly, and clinically diverse tumors, the mainstays of meningioma treatment remain maximal safe resection and radiation therapy. The aim of this review of meningioma radiotherapy is to provide a concise summary of the history, current evidence, and future for application of radiotherapy in meningioma treatment.
October 31, 2022: Journal of Neuro-oncology
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