Genetic Phenomena Commons^™

Unraveling The Hidden Complexity Of Cancer Through Long-Read Sequencing, Qiuhui Li, Ayse G Keskus, Justin Wagner, Michal B Izydorczyk, Winston Timp, Fritz J Sedlazeck, Alison P Klein, Justin M Zook, Mikhail Kolmogorov, Michael C Schatz

Faculty, Staff and Students Publications

Cancer is fundamentally a disease of the genome, characterized by extensive genomic, transcriptomic, and epigenomic alterations. Most current studies predominantly use short-read sequencing, gene panels, or microarrays to explore these alterations; however, these technologies can systematically miss or misrepresent certain types of alterations, especially structural variants, complex rearrangements, and alterations within repetitive regions. Long-read sequencing is rapidly emerging as a transformative technology for cancer research by providing a comprehensive view across the genome, transcriptome, and epigenome, including the ability to detect alterations that previous technologies have overlooked. In this Perspective, we explore the current applications of long-read sequencing for both …

Proteogenomic Characterization Of Non-Functional Pancreatic Neuroendocrine Tumors Unravels Clinically Relevant Subgroups, Shunrong Ji, Lihua Cao, Jing Gao, Yang Du, Zeng Ye, Xin Lou, Fen Liu, Yehan Zhang, Junfeng Xu, Xiaohan Shi, Huan Wang, Penghao Li, Yikai Li, Hongxu Chen, Zhicheng Yang, Suizhi Gao, Wuhu Zhang, Dan Huang, Shujuan Ni, Miaoyan Wei, Fei Wang, Yan Wang, Tian Ding, Desheng Jing, Guixiong Fan, Zhiyun Gong, Renquan Lu, Yi Qin, Jie Chen, Xiaowu Xu, Pei Wang, Bing Zhang, Li Ding, Ana I Robles, Henry Rodriguez, David K Chang, Ralph H Hruban, Dong Gao, Daming Gao, Gang Jin, Hu Zhou, Jianmin Wu, Xianjun Yu

Faculty, Staff and Students Publications

The majority of neuroendocrine neoplasms in pancreas are non-functional pancreatic neuroendocrine tumors (NF-PanNETs), which exhibit a high occurrence of distant metastases with limited therapeutic options. Here, we perform a comprehensive molecular characterization of 108 NF-PanNETs through integrative analysis of genomic, transcriptomic, proteomic, and phosphoproteomic profiles. Proteogenomic analysis provides functional insights into the genomic driver alterations of NF-PanNETs, revealing a potential mediator of MEN1 alterations using Men1-conditional knockout mice. Machine-learning-based modeling uncovers a three-protein signature as an independent prognostic factor, which is validated by an independent external cohort. Proteomic and phosphoproteomic-based stratification identifies four subtypes with distinct molecular characteristics, immune microenvironments, …

Natural Killer Cells’ Functional Impairment Drives The Immune Escape Of Pre-Malignant Clones In Early-Stage Myelodysplastic Syndromes, Juan Jose Rodriguez-Sevilla, Irene Ganan-Gomez, Bijender Kumar, Natthakan Thongon, Feiyang Ma, Kelly S Chien, Yi J Kim, Hui Yang, Sanam Loghavi, Roselyn Tan, Vera Adema, Zongrui Li, Tomoyuki Tanaka, Hidetaka Uryu, Rashmi Kanagal-Shamanna, Gheath Al-Atrash, Rafael Bejar, Pinaki Prosad Banerjee, Sophia Lynn Cha, Guillermo Montalban-Bravo, Max Dougherty, Maria Claudina Fernandez Laurita, Noelle Wheeler, Baosen Jia, Eirini P Papapetrou, Franco Izzo, Daniela E Dueñas, Salome Mcallen, Yiqian Gu, Gabriele Todisco, Francesca Ficara, Matteo Giovanni Della Porta, Abhinav Jain, Koichi Takahashi, Karen Clise-Dwyer, Stephanie Halene, Maria Teresa Sabrina Bertilaccio, Guillermo Garcia-Manero, May Daher, Simona Colla

Faculty, Staff and Student Publications

Dissecting the preneoplastic disease states' biological mechanisms that precede tumorigenesis can lead to interventions that can slow down disease progression and/or mitigate disease-related comorbidities. Myelodysplastic syndromes (MDS) cannot be cured by currently available pharmacological therapies, which fail to eradicate aberrant hematopoietic stem cells (HSCs), most of which are mutated by the time of diagnosis. Here, we sought to elucidate how MDS HSCs evade immune surveillance and expand in patients with clonal cytopenias of undetermined significance (CCUS), the pre-malignant stage of MDS. We used multi-omic single-cell approaches and functional in vitro studies to show that immune escape at disease initiation is …

Allosteric Targeted Drug Delivery For Enhanced Blood-Brain Barrier Penetration Via Mimicking Transmembrane Domain Interactions, Kaicheng Tang, Zhongjie Tang, Miaomiao Niu, Zuyin Kuang, Weiwei Xue, Xinyu Wang, Xinlong Liu, Yang Yu, Seongdong Jeong, Yifan Ma, Annette Wu, Betty Y S Kim, Wen Jiang, Zhaogang Yang, Chong Li

Faculty, Staff and Student Publications

Current strategies for active targeting in the brain are entirely based on the effective interaction of the ligand with the orthosteric sites of specific receptors on the blood-brain barrier (BBB), which is highly susceptible to various pathophysiological factors and limits the efficacy of drug delivery. Here, we propose an allosteric targeted drug delivery strategy that targets classical BBB transmembrane receptors by designing peptide ligands that specifically bind to their transmembrane domains. This strategy prevents competitive interference from endogenous ligands and antibodies by using the insulin receptor and integrin α

An Open-Label Study Evaluating The Safety And Efficacy Of Amo-01 For The Treatment Of Seizures In Phelan-Mcdermid Syndrome, Tess Levy, J Lloyd Holder, Joseph P Horrigan, Michael F Snape, Alison Mcmorn, Christina Layton, Hailey Silver, Kate Friedman, Hannah Grosman, Slayton Underwood, Danielle Halpern, Jessica Zweifach, Paige M Siper, Alexander Kolevzon

Duncan NRI Faculty and Staff Publications

Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder caused by haploinsufficiency of the SHANK3 gene. Approximately 25% of individuals with PMS have epilepsy. Treatment of epilepsy in PMS may require multiple anticonvulsants, and in a minority of cases, seizures remain poorly controlled. Converging lines of evidence in different experimental models indicate that the Ras-ERK pathway is implicated in the pathophysiology of seizure generation and neurobehavioral symptoms in PMS. The goal of this study was to evaluate the safety, tolerability, and efficacy in treating seizures in adults and adolescents with PMS using AMO-01, a Ras-ERK pathway inhibitor. A single 6-hour intravenous infusion …

Her2-Selective Tyrosine Kinase Inhibitor, Zongertinib (Bi 1810631), In Patients With Advanced/Metastatic Solid Tumors With Her2 Alterations: A Phase Ia Dose-Escalation Study, John V Heymach, Frans Opdam, Minal Barve, Hai-Yan Tu, Yi-Long Wu, David Berz, Lukas Schröter, Yanick Botilde, Behbood Sadrolhefazi, Josep Serra, Kiyotaka Yoh, Noboru Yamamoto

Faculty, Staff and Student Publications

Purpose: Human epidermal growth factor receptor 2 (HER2) alterations occur in many solid cancers, including non-small cell lung cancer (NSCLC). Beamion LUNG-1 (ClinicalTrials.gov identifier: NCT04886804) is assessing the safety/efficacy of zongertinib (BI 1810631), a novel HER2-selective tyrosine kinase inhibitor that spares epidermal growth factor receptor, in patients with HER2-altered solid tumors.

Materials and methods: Beamion LUNG-1 is an ongoing multicenter, multicohort phase Ia/Ib trial. Phase Ia assessed zongertinib administered twice a day (15-150 mg) or once daily (60-360 mg) in pretreated patients with various tumors, including NSCLC. Primary end points were maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs); …

Geographic Divergence Of Methicillin-Resistant Staphylococcus Aureus St5-Scc Mec I In The Aftermath Of A Major Earthquake And Tsunami: Impact Of A Plasmid Harboring Heavy Metal Resistance Genes, Jose R W Martínez, Manuel Alcalde-Rico, Estefanía Jara-Videla, Jinnethe Reyes, Lina P Carvajal, Sandra Rincon, Rafael Ríos, Lorena Diaz, Ana Quesille-Villalobos, Roberto Riquelme-Neira, Lina Rivas, Ahmed M Moustafa, Blake Hanson, Eduardo A Undurraga, Jorge Olivares-Pacheco, Patricia García, Rafael Araos, Paul J Planet, César A Arias, Jose M Munita

Faculty, Staff and Student Publications

Methicillin-resistant Staphylococcus aureus (MRSA) is a major public health menace. The global spread of MRSA is characterized by successive waves of epidemic clones dominating specific geographical regions. The acquisition of genes encoding resistance to heavy metals (HMRGs) is thought to be a key feature in the geographic divergence of MRSA. However, the cause-effect relationship between the presence of HMRGs and the divergence of MRSA clones remains to be clarified. In this study, we assessed the role that HMRGs may have played in the evolutionary divergence of the MRSA ST5-SCCmecI lineage in Latin America. We conducted a genomic characterization …

Identifying The Human Olfactory And Chemosignaling Neural Networks Using Event Related Fmri And Graph Theory, Saideh Ferdowsi, Tom Foulsham, Alireza Rahmani, Dimitri Ognibene, Luca Citi, Wen Li

Faculty, Staff and Student Publications

This study aims to characterize and compare the functional neural networks associated with different olfactory stimuli, including air, non-social odours, and human body odours. We introduce a novel processing pipeline based on event-related functional magnetic resonance imaging (fMRI) and graph theory for network identification. To ensure the stability and small worldness of the characterized networks, we conduct statistical validations, network modularity assessments, and robustness measurement against local attacks. The key hypothesis is that human body odours (so-called social odours) and non-social odours engage distinct neural networks, particularly in regions responsible for social processing. We found that the posterior medial orbitofrontal …

Phase 2 Trial Of Ibrutinib And Nivolumab In Patients With Relapsed Cns Lymphomas, Dai Chihara, Raphael E Steiner, Ranjit Nair, Lei Feng, Sairah Ahmed, Paolo Strati, Luis Malpica, Donna P Griffith, Shivon A Mathew, Wirt Montinez, Gita Masand, Felipe Samaniego, Maria A Rodriguez, Fredrick B Hagemeister, Luis E Fayad, Swaminathan P Iyer, Loretta J Nastoupil, Sattva S Neelapu, Christopher R Flowers, Jason R Westin

Faculty, Staff and Student Publications

Treatment options are limited for both relapsed/refractory primary and secondary central nervous system (CNS) lymphoma and the prognosis remains poor. Previous studies have shown the activity of Bruton tyrosine kinase inhibitors and programmed death-1-targeted therapies in CNS lymphoma, and studies suggested potential synergy. Therefore, we conducted a phase 2 trial that combined ibrutinib with nivolumab for patients with relapsed/refractory CNS lymphoma. Patients received 560 mg oral ibrutinib daily with 240 mg IV nivolumab every 14 days (28 days per cycle). Patients who had partial or complete response after 6 cycles of treatment could continue therapy for up to 2 years …

Life On The Dry Side: A Roadmap To Understanding Desiccation Tolerance And Accelerating Translational Applications, R A Marks, J T B Ekwealor, M A S Artur, L Bondi, T C Boothby, O M S Carmo, D C Centeno, K K Coe, H J W Dace, S Field, A Hutt, S Porembski, A Thalhammer, L Van Der Pas, A J Wood, P Alpert, D Bartels, S Boeynaems, M N Datar, T Giese, W I Seidou, S M Kirchner, J Köhler, U G V S S Kumara, J Kyung, R Lyall, B D Mishler, J B V T Ndongmo, M S Otegui, V Reddy, J Rexroth, S M Tebele, R Vanburen, J Verdier, U C Vothknecht, M F Wittenberg, E Zokov, M J Oliver, S Y Rhee

Duncan NRI Faculty and Staff Publications

To thrive in extreme conditions, organisms have evolved a diverse arsenal of adaptations that confer resilience. These species, their traits, and the mechanisms underlying them comprise a valuable resource that can be mined for numerous conceptual insights and applied objectives. One of the most dramatic adaptations to water limitation is desiccation tolerance. Understanding the mechanisms underlying desiccation tolerance has important potential implications for medicine, biotechnology, agriculture, and conservation. However, progress has been hindered by a lack of standardization across sub-disciplines, complicating the integration of data and slowing the translation of basic discoveries into practical applications. Here, we synthesize current knowledge …

Tobacco Smoke Exposure Is A Driver Of Altered Oxidative Stress Response And Immunity In Head And Neck Cancer, Yang Li, Pedram Yadollahi, Fonma N Essien, Vasanta Putluri, Chandra Shekar R Ambati, Karthik Reddy Kami Reddy, Abu Hena Mostafa Kamal, Nagireddy Putluri, Lama M Abdurrahman, Maria E Ruiz Echartea, Keenan J Ernste, Akshar J Trivedi, Jonathan Vazquez-Perez, William H Hudson, William K Decker, Rutulkumar Patel, Abdullah A Osman, Farrah Kheradmand, Stephen Y Lai, Jeffrey N Myers, Heath D Skinner, Cristian Coarfa, Kwangwon Lee, Antrix Jain, Anna Malovannaya, Mitchell J Frederick, Vlad C Sandulache

Faculty, Staff and Student Publications

Background: Exposomes are critical drivers of carcinogenesis. However, how they modulate tumor behavior remains unclear. Extensive clinical data show cigarette smoke to be a key exposome that promotes aggressive tumors, higher rates of metastasis, reduced response to chemoradiotherapy, and suppressed anti-tumor immunity. We sought to determine whether smoke itself can modulate aggressive tumor behavior in head and neck squamous cell carcinoma (HNSCC) through reprogramming of the cellular reductive state.

Methods: Using established human and murine HNSCC cell lines and syngeneic mouse models, we utilized conventional western blotting, steady state and flux metabolomics, RNA sequencing, quantitative proteomics and flow cytometry to …

A Phase Ii Trial Of Sitravatinib + Nivolumab After Progression On Immune Checkpoint Inhibitor In Patients With Metastatic Clear Cell Rcc, Andrew W Hahn, Nabil Adra, Ulka Vaishampayan, Lianchun Xiao, Nazli Dizman, Ying Yuan, Sagar S Mukhida, Matthew T Campbell, Jianjun Gao, Amado J Zurita, Eric Jonasch, Nizar M Tannir, Amishi Y Shah, Pavlos Msaouel

Faculty, Staff and Student Publications

Background: Sitravatinib, an oral multi-kinase inhibitor targeting VEGFR, TAM, and MET, has been shown to resensitize the tumor microenvironment to immune checkpoint inhibitors (ICI) by reducing immune-suppressive myeloid cells in metastatic clear cell RCC (ccRCC). ICI is the standard first-line (1L) treatment of metastatic ccRCC, and there is unmet need for improved treatment outcomes after progression on ICI. We hypothesized that sitravatinib plus nivolumab would revert an immunosuppressive tumor microenvironment (TME) to improve clinical outcomes.

Methods: In this investigator-initiated, phase II, multicenter trial (NCT04904302), patients with progressive metastatic ccRCC after 1-2 lines of treatment were enrolled into 3 …

K-Mer Analysis Of Long-Read Alignment Pileups For Structural Variant Genotyping, Adam C English, Fabio Cunial, Ginger A Metcalf, Richard A Gibbs, Fritz J Sedlazeck

Faculty, Staff and Students Publications

Accurately genotyping structural variant (SV) alleles is crucial to genomics research. We present a novel method (kanpig) for genotyping SVs that leverages variant graphs and k-mer vectors to rapidly generate accurate SV genotypes. Benchmarking against the latest SV datasets shows kanpig achieves a single-sample genotyping concordance of 82.1%, significantly outperforming existing tools, which average 66.3%. We explore kanpig's use for multi-sample projects by testing on 47 genetically diverse samples and find kanpig accurately genotypes complex loci (e.g. SVs neighboring other SVs), and produces higher genotyping concordance than other tools. Kanpig requires only 43 seconds to process a single sample's 20x …

De Novo Variants In Cdkl1 And Cdkl2 Are Associated With Neurodevelopmental Symptoms, Ali H Bereshneh, Jonathan C Andrews, Daniel F Eberl, Guney Bademci, Nicholas A Borja, Stephanie Bivona, Wendy K Chung, Shinya Yamamoto, Michael F Wangler, Shane Mckee, Mustafa Tekin, Hugo J Bellen, Oguz Kanca

Duncan NRI Faculty and Staff Publications

The CDKL (cyclin-dependent kinase-like) family consists of five members in humans, CDKL1-5, that encode serine-threonine kinases. The only member that has been associated with a Mendelian disorder is CDKL5, and variants in CDKL5 cause developmental and epileptic encephalopathy type 2 (DEE2). Here, we study four de novo variants in CDKL2 identified in five individuals, including three unrelated probands and monozygotic twins. These individuals present with overlapping symptoms, including global developmental delay, intellectual disability, childhood-onset epilepsy, dyspraxia, and speech deficits. We also identified two individuals with de novo missense variants in CDKL1 in the published Deciphering Developmental Disorders (DDD) and GeneDx …

Hif Regulates Multiple Translated Endogenous Retroviruses: Implications For Cancer Immunotherapy, Qinqin Jiang, David A Braun, Karl R Clauser, Vijyendra Ramesh, Nitin H Shirole, Joseph E Duke-Cohan, Nancy Nabilsi, Nicholas J Kramer, Cleo Forman, Isabelle E Lippincott, Susan Klaeger, Kshiti M Phulphagar, Vipheaviny Chea, Nawoo Kim, Allison P Vanasse, Eddy Saad, Teagan Parsons, Melissa Carr-Reynolds, Isabel Carulli, Katarina Pinjusic, Yijia Jiang, Rong Li, Sudeepa Syamala, Suzanna Rachimi, Eva K Verzani, Jonathan D Stevens, William J Lane, Sabrina Y Camp, Kevin Meli, Melissa B Pappalardi, Zachary T Herbert, Xintao Qiu, Paloma Cejas, Henry W Long, Sachet A Shukla, Eliezer M Van Allen, Toni K Choueiri, L Stirling Churchman, Jennifer G Abelin, Cagan Gurer, Gavin Macbeath, Richard W Childs, Steven A Carr, Derin B Keskin, Catherine J Wu, William G Kaelin

Faculty, Staff and Student Publications

Clear cell renal cell carcinoma (ccRCC), despite having a low mutational burden, is considered immunogenic because it occasionally undergoes spontaneous regressions and often responds to immunotherapies. The signature lesion in ccRCC is inactivation of the VHL tumor suppressor gene and consequent upregulation of the HIF transcription factor. An earlier case report described a ccRCC patient who was cured by an allogeneic stem cell transplant and later found to have donor-derived T cells that recognized a ccRCC-specific peptide encoded by a HIF-responsive endogenous retrovirus (ERV), ERVE-4. We report that ERVE-4 is one of many ERVs that are induced by HIF, translated …

Clinical Validation Of Rna Sequencing For Mendelian Disorder Diagnostics, Sen Zhao, Kristina Macakova, Jefferson C Sinson, Hongzheng Dai, Jill Rosenfeld, Gladys E Zapata, Shenglan Li, Patricia A Ward, Christiana Wang, Chunjing Qu, Becky Maywald, Brendan Lee, Christine Eng, Pengfei Liu

Faculty, Staff and Students Publications

Despite rapid advancements in clinical sequencing, over half of diagnostic evaluations still lack definitive results. RNA sequencing (RNA-seq) has shown promise in research settings for bridging this gap by providing essential functional data for accurate interpretation of diagnostic sequencing results. However, despite advanced research pipelines, clinical translation of diagnostic RNA-seq has not yet been realized. We have developed and validated a clinical diagnostic RNA-seq test for individuals with suspected genetic disorders who have existing or concurrent comprehensive DNA diagnostic testing. This diagnostic RNA-seq test processes RNA samples from fibroblasts or blood and derives clinical interpretations based on the analytical detection …

Chronic Viral Mimicry Induction Following P53 Loss Promotes Immune Evasion, Charles A Ishak, Sajid A Marhon, Naïri Tchrakian, Anjelica Hodgson, Helen Loo Yau, Isabela M Gonzaga, Melanie Peralta, Ilinca M Lungu, Stephanie Gomez, Sheng-Ben Liang, Shu Yi Shen, Raymond Chen, Jocelyn Chen, Biji Chatterjee, Kevin N Wanniarachchi, Junwoo Lee, Nicholas Zehrbach, Amir Hosseini, Parinaz Mehdipour, Siyu Sun, Alexander Solovyov, Ilias Ettayebi, Kyle E Francis, Aobo He, Taiyi Wu, Shengrui Feng, Tiago Da Silva Medina, Felipe Campos De Almeida, Jane Bayani, Jason Li, Spencer Macdonald, Yadong Wang, Sarah S Garcia, Elisa Arthofer, Noor Diab, Aneil Srivastava, Paul Tran Austin, Peter J B Sabatini, Benjamin D Greenbaum, Catherine A O'Brien, Trevor G Shepherd, Ming Sound Tsao, Katherine B Chiappinelli, Amit M Oza, Blaise A Clarke, Robert Rottapel, Stephanie Lheureux, Daniel D De Carvalho

Faculty, Staff and Student Publications

Epigenetic therapies facilitate transcription of immunogenic repetitive elements that cull cancer cells through ‘viral mimicry’ responses. Paradoxically, cancer-initiating events also facilitate transcription of repetitive elements. Contributions of repetitive element transcription towards cancer initiation, and the mechanisms by which cancer cells evade lethal viral mimicry responses during tumor initiation remain poorly understood. In this report, we characterize premalignant lesions of the fallopian tube along with syngeneic epithelial ovarian cancer models to explore the earliest events of tumorigenesis following loss of the p53 tumor suppressor protein. We report that p53 loss permits transcription of immunogenic repetitive elements and chronic viral mimicry activation …

Conformal Predictive Intervals In Survival Analysis: A Resampling Approach, Jing Qin, Jin Piao, Jing Ning, Yu Shen

Faculty, Staff and Student Publications

The distribution-free method of conformal prediction has gained considerable attention in computer science, machine learning, and statistics. Candès et al. extended this method to right-censored survival data, addressing right-censoring complexity by creating a covariate shift setting, extracting a subcohort of subjects with censoring times exceeding a fixed threshold. Their approach only estimates the lower prediction bound for type I censoring, where all subjects have available censoring times regardless of their failure status. In medical applications, we often encounter more general right-censored data, observing only the minimum of failure time and censoring time. Subjects with observed failure times have unavailable censoring …

Identifiability And Model Selection Frameworks For Models Of High-Grade Glioma Response To Chemoradiation, Khushi C Hiremath, Kenan Atakishi, Ernesto A B F Lima, Maguy Farhat, Bikash Panthi, Holly Langshaw, Mihir D Shanker, Wasif Talpur, Sara Thrower, Jodi Goldman, Caroline Chung, Thomas E Yankeelov, David A Hormuth Ii

Faculty, Staff and Student Publications

We have developed a family of biology-based mathematical models of high-grade glioma (HGG), capturing the key features of tumour growth and response to chemoradiation. We now seek to quantify the accuracy of parameter estimation and determine, when given a virtual patient cohort, which model was used to generate the tumours. In this way, we systematically test both the parameter and model identifiability. Virtual patients are generated from unique growth parameters whose growth dynamics are determined by the model family. We then assessed the ability to recover model parameters and select the model used to generate the tumour. We then evaluated …

Long-Term Patient-Reported Bowel And Urinary Quality Of Life In Patients Treated With Intensity-Modulated Radiotherapy Versus Intensity-Modulated Proton Therapy For Localized Prostate Cancer, Kimberly R Gergelis, Miao Bai, Jiasen Ma, David M Routman, Bradley J Stish, Brian J Davis, Thomas M Pisansky, Thomas J Whitaker, Richard Choo

Faculty, Staff and Student Publications

Purpose: This study aimed to compare long-term patient-reported outcomes in bowel and urinary domains between intensity-modulated radiotherapy (IMRT) and intensity-modulated proton therapy (IMPT) for localized prostate cancer.

Methods and materials: Patients with clinical T1-T2 prostate cancer receiving IMRT or IMPT at a tertiary cancer center from 2015-2018 were analyzed to determine the changes in the prospectively collected bowel function (BF), urinary irritative/obstructive symptoms (UO), and urinary incontinence (UI) domains of EPIC-26. The mean changes in EPIC-26 scores were evaluated from pretreatment to 24 months post-radiotherapy for each modality. A score change >50% of the baseline standard deviation was considered a …

Glucose Uptake In Pigment Glia Suppresses Tau-Induced Inflammation And Photoreceptor Degeneration, Mikiko Oka, Sho Nakajima, Emiko Suzuki, Shinya Yamamoto, Kanae Ando

Duncan NRI Faculty and Staff Publications

Brain inflammation contributes to the pathogenesis of neurodegenerative diseases, such as Alzheimer's disease (AD). Glucose hypometabolism and glial activation are pathological features seen in AD brains; however, the connection between the two is not fully understood. Using a Drosophila model of AD, we identified that glucose metabolism in glia plays a critical role in neuroinflammation under disease conditions. Expression of human MATP (hereafter referred to as Tau) in the retinal cells, including photoreceptor neurons and pigment glia, causes photoreceptor degeneration accompanied by the formation of dark-stained round inclusion-like structures and swelling of the lamina cortex. We found that inclusion-like structures …

De Novo Variants In Rybp Are Associated With A Severe Neurodevelopmental Disorder And Congenital Anomalies, Monika Weisz-Hubshman, Lindsay C Burrage, Sharayu V Jangam, Jill A Rosenfeld, Sandra Von Hardenberg, Anke Bergmann, Manuela Friederike Richter, Malgorzata Rydzanicz, Rafal Ploski, Agnieszka Stembalska, Wendy K Chung, Rebecca R Hernan, Foong Y Lim, Theresa Brunet, Steffen Syrbe, Boris Keren, Solveig Heide, David R Murdock, Hongzheng Dai, Fan Xia, Shamika Ketkar, Brian Dawson, Vinodh Narayanan, Hillary K Graves, Undiagnosed Diseases Network, Michael F Wangler, Carlos Bacino, Brendan Lee

Duncan NRI Faculty and Staff Publications

Purpose: Polycomb group proteins are key epigenetic transcriptional regulators. Multiple neurodevelopmental disorders are associated with pathogenic variants of the genes encoding Polycomb group proteins. RYBP is a core component of the noncanonical Polycomb Repressor Complex 1; however, its role in disease is unclear.

Methods: Functional consequences of RYBP variants were assessed using in vitro cellular and in vivo Drosophila melanogaster studies.

Results: We described 7 individuals with heterozygous de novo variants of RYBP and their clinical findings, including severe developmental delay, dysmorphisms, and multiple congenital anomalies. We showed that all single-nucleotide variants in RYBP localize to the N-terminal domain of …

Nicotinic Acetylcholine Receptor Expression In Merkel Cell Carcinoma Is Associated With Clinical And Histopathologic Parameters, Christopher R Cunningham, Yiannis P Dimopoulos, Ian M García-Quiñones, Denái R Milton, Manuel Delgado-Vélez, Woo Cheal Cho, Victor G Prieto, José A Lasalde-Dominicci, Leomar Y Ballester, Phyu P Aung

Faculty, Staff and Student Publications

Background: Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy with neuroendocrine differentiation. Several molecular pathways have been implicated in MCC development and multiple cell-of-origin candidates have been proposed, including neural crest cells, which express acetylcholine receptors (AChRs). The role of nicotinic acetylcholine receptors (nAChRs) in MCC has not been explored. In this study, we investigated if MCC expresses nAChRs and if nAChR expression correlates with patient characteristics.

Methods: The study included 71 MCC cases diagnosed with sufficient tissue available to perform immunohistochemical analysis. The median follow-up was 29.8 months (range, 2.7-234.1). We performed immunohistochemistry using antibodies against the …

Nicotinic Acetylcholine Receptor Expression In Merkel Cell Carcinoma Is Associated With Clinical And Histopathologic Parameters, Christopher R Cunningham, Yiannis P Dimopoulos, Ian M García-Quiñones, Denái R Milton, Manuel Delgado-Vélez, Woo Cheal Cho, Victor G Prieto, José A Lasalde-Dominicci, Leomar Y Ballester, Phyu P Aung

Faculty, Staff and Student Publications

Background: Merkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy with neuroendocrine differentiation. Several molecular pathways have been implicated in MCC development and multiple cell-of-origin candidates have been proposed, including neural crest cells, which express acetylcholine receptors (AChRs). The role of nicotinic acetylcholine receptors (nAChRs) in MCC has not been explored. In this study, we investigated if MCC expresses nAChRs and if nAChR expression correlates with patient characteristics.

Methods: The study included 71 MCC cases diagnosed with sufficient tissue available to perform immunohistochemical analysis. The median follow-up was 29.8 months (range, 2.7-234.1). We performed immunohistochemistry using antibodies against the …

Lysyl Hydroxylase 2 Glucosylates Collagen Vi To Drive Lung Cancer Progression, Shike Wang, Houfu Guo, Reo Fukushima, Masahiko Terajima, Min Liu, Guan-Yu Xiao, Lenka Koudelková, Chao Wu, Xin Liu, Jiang Yu, Emma Burris, Jun Xu, Alvise Schiavinato, William K Russell, Mitsuo Yamauchi, Xiaochao Tan, Jonathan M Kurie

Faculty, Staff and Student Publications

Lysyl hydroxylase 2 (LH2) is highly expressed in multiple tumor types and accelerates disease progression by hydroxylating lysine residues on fibrillar collagen telopeptides to generate stable collagen cross links in tumor stroma. Here, we show that a galactosylhydroxylysyl glucosyltransferase (GGT) domain on LH2-modified type-VI collagen (Col6) to promote lung adenocarcinoma (LUAD) growth and metastasis. In tumors generated by LUAD cells lacking LH2 GGT domain activity, stroma was less stiff, and stable types of collagen cross links were reduced. Mass spectrometric analysis of total and glycosylated peptides in parental and GGT-inactive tumor samples identified Col6 chain α3 (Col6a3), a component of …

In Vivo Antibody Labeling Route And Fluorophore Dictate Labeling Efficiency, Sensitivity, And Longevity, Natalie B Hagan, Charles Inaku, Nikesh Kunder, Tayleur White, Thierry Iraguha, Anna Meyer, Kristen E Pauken, Jason M Schenkel

Faculty, Staff and Student Publications

Leukocytes migrate through the blood and extravasate into organs to surveil the host for infection or cancer. Recently, we demonstrated that intravenous (IV) anti-CD45.2 antibody labeling allowed for precise tracking of leukocyte migration. However, the narrow labeling window can make this approach challenging for tracking rare migration events. Here, we show that altering antibody administration route and fluorophore can significantly extend the antibody active labeling time. We found that while both IV and intraperitoneal (IP) anti-CD45.2 antibody labeled circulating leukocytes after injection, they had different kinetic properties that impacted labeling time and intensity. Quantification of circulating antibody revealed that while …

Lesion Classification By Model-Based Feature Extraction: A Differential Affine Invariant Model Of Soft Tissue Elasticity In Ct Images, Weiguo Cao, Marc J Pomeroy, Zhengrong Liang, Yongfeng Gao, Yongyi Shi, Jiaxing Tan, Fangfang Han, Jing Wang, Jianhua Ma, Hongbin Lu, Almas F Abbasi, Perry J Pickhardt

Faculty, Staff and Student Publications

The elasticity of soft tissues has been widely considered a characteristic property for differentiation of healthy and lesions and, therefore, motivated the development of several elasticity imaging modalities, for example, ultrasound elastography, magnetic resonance elastography, and optical coherence elastography to directly measure the tissue elasticity. This paper proposes an alternative approach of modeling the elasticity for prior knowledge-based extraction of tissue elastic characteristic features for machine learning (ML) lesion classification using computed tomography (CT) imaging modality. The model describes a dynamic non-rigid (or elastic) soft tissue deformation in differential manifold to mimic the tissues’ elasticity under wave fluctuation in vivo. …

Vitamin D-Related Genetic Variants And Prostate Cancer Risk In Black Men, Tracy M Layne, Joseph H Rothstein, Xiaoyu Song, Shaneda Warren Andersen, Emma K T Benn, Weiva Sieh, Robert J Klein

Faculty, Staff and Student Publications

Background: The relationship between vitamin D and prostate cancer has primarily been characterized among White men. Black men, however, have higher prostate cancer incidence and mortality rates, chronically low circulating vitamin D levels, and ancestry-specific genetic variants in vitamin D-related genes. Here, we examine critical genes in the vitamin D pathway and prostate cancer risk in Black men.

Methods: We assessed a total of 73 candidate variants in genes (namely GC, CYP27A1, CYP27B1, CYP24A1, VDR, and RXRA) including functional variants previously associated with prostate cancer and circulating 25(OHD) in White men. Associations with prostate cancer risk were examined using genome-wide …

The Effect Of Alzheimer's Disease Genetic Factors On Limbic White Matter Microstructure, Anna Lorenz, Aditi Sathe, Dimitrios Zaras, Yisu Yang, Alaina Durant, Michael E Kim, Chenyu Gao, Nancy R Newlin, Karthik Ramadass, Praitayini Kanakaraj, Nazirah Mohd Khairi, Zhiyuan Li, Tianyuan Yao, Yuankai Huo, Logan Dumitrescu, Niranjana Shashikumar, Kimberly R Pechman, Trevor Bryan Jackson, Abigail W Workmeister, Shannon L Risacher, Lori L Beason-Held, Yang An, Konstantinos Arfanakis, Guray Erus, Christos Davatzikos, Mohamad Habes, Di Wang, Duygu Tosun, Arthur W Toga, Paul M Thompson, Elizabeth C Mormino, Panpan Zhang, Kurt Schilling, Marilyn Albert, Walter Kukull, Sarah A Biber, Bennett A Landman, Sterling C Johnson, Barbara Bendlin, Julie Schneider, Lisa L Barnes, David A Bennett, Angela L Jefferson, Susan M Resnick, Andrew J Saykin, Timothy J Hohman, Derek B Archer

Faculty, Staff and Student Publications

Introduction: White matter (WM) microstructure is essential for brain function but deteriorates with age and in neurodegenerative conditions such as Alzheimer's disease (AD). Diffusion MRI, enhanced by advanced bi-tensor models accounting for free water (FW), enables in vivo quantification of WM microstructural differences.

Methods: To evaluate how AD genetic risk factors affect limbic WM microstructure - crucial for memory and early impacted in disease - we conducted linear regression analyses in a cohort of 2,614 non-Hispanic White aging adults (aged 50.12 to 100.85 years). The study evaluated 36 AD risk variants across 26 genes, the association between AD polygenic scores …

Il13rα2-Targeting Antibodies For Immuno-Pet In Solid Malignancies, Leah Gajecki, Irina V Lebedeva, Yu-Rou Liao, Daisy Ambriz, Lukas M Carter, Melina Kumpf, Samantha Lovibond, Justin S Hachey, Maya S Graham, Michael Postow, Jason S Lewis, David P Andrew, Manuel Baca, Heiko Schöder, Steven M Larson, Darren R Veach, Simone Krebs

Faculty, Staff and Student Publications

Interleukin-13 receptor α-2 (IL13Rα2) is a cell surface receptor frequently expressed in solid malignancies, such as glioblastoma and melanoma, with limited expression in healthy tissue, rendering it an ideal target for noninvasive and specific tumor delineation. In this study, we report the development of 5 novel IL13Rα2-targeted human monoclonal antibodies (mAbs) KLG-1-5; in subsequent in vitro and in vivo studies after radiolabeling with 89Zr, we evaluate their performance to identify a lead candidate.

Methods: Five novel human anti-IL13Rα2 mAbs KLG-1-5 were developed and in vitro binding properties and target specificity assessed. In vivo 89Zr-immuno-PET using KLG-1-5 was conducted in a …