Medical Specialties Commons^™

Long-Read Single-Cell Rna Sequencing Enables The Study Of Cancer Subclone-Specific Genotypes And Phenotypes In Chronic Lymphocytic Leukemia, Gage S Black, Xiaomeng Huang, Yi Qiao, Philip Moos, Deepa Sampath, Deborah M Stephens, Jennifer A Woyach, Gabor T Marth

Faculty, Staff and Student Publications

Bruton tyrosine kinase (BTK) inhibitors are effective for the treatment of chronic lymphocytic leukemia (CLL) due to BTK's role in B cell survival and proliferation. Treatment resistance is most commonly caused by the emergence of the hallmark BTKC481S mutation that inhibits drug binding. In this study, we aimed to investigate cancer subclones harboring a BTKC481S mutation and identify cells with co-occurring CLL driver mutations. In addition, we sought to determine whether BTK-mutated subclones exhibit distinct transcriptomic behavior when compared to other cancer subclones. To achieve these goals, we use scBayes, which integrates bulk DNA sequencing and single-cell …

Results Of The Phase I/Ii Study And Preliminary B-Cell Gene Signature Of Combined Inhibition Of Glutamine Metabolism And Egfr In Colorectal Cancer, Kristen K Ciombor, Seong-Woo Bae, Jennifer G Whisenant, Gregory D Ayers, Quanhu Sheng, Todd E Peterson, Gary T Smith, Kangyu Lin, Saikat Chowdhury, Preeti Kanikarla Marie, Alexey Sorokin, Allison S Cohen, Laura W Goff, Dana B Cardin, John Paul Shen, Scott Kopetz, Cathy Eng, Yu Shyr, Jordan Berlin, H Charles Manning

Faculty, Staff and Student Publications

Purpose: EGFR-targeting mAbs are essential for managing rat sarcoma virus wild-type metastatic colorectal cancer (mCRC), but their limited efficacy necessitates exploring immunologic and metabolic factors influencing response. This study evaluated glutamine metabolism targeting with EGFR inhibition to identify response biomarkers in patients with prior anti-EGFR treatment progression.

Patients and methods: We conducted a phase I/II trial in patients with KRAS wild-type mCRC, combining panitumumab (6 mg/kg) and CB-839 (600 mg/kg or 800 mg/kg), hypothesizing that the dual inhibition of glutamine metabolism and MAPK signaling would enhance outcomes. As study correlatives, we investigated the B-cell activation signature "B-score" and glutamine PET …

Closing The Gaps, And Improving Somatic Structural Variant Analysis And Benchmarking Using Chm13-T2t, Luis F Paulin, Jeremy Fan, Kieran O'Neill, Erin Pleasance, Vanessa L Porter, Steven J M Jones, Fritz J Sedlazeck

Faculty, Staff and Students Publications

The complexities of cancer genomes are becoming more easily interpreted due to advancements in sequencing technologies and improved bioinformatic analysis. Structural variants (SVs) represent an important subset of somatic events in tumors. While the detection of SVs has been markedly improved by the development of long-read sequencing, somatic variant identification and annotation remain challenging. We hypothesized that the use of a completed human reference genome (CHM13-T2T) would improve somatic SV calling. Our findings in a tumor-normal matched benchmark sample and three patient samples show that the CHM13-T2T improves SV detection accuracy compared to GRCh38 with a notable reduction in false-positive …

Update On Cancer And Central Nervous System Tumor Surveillance In Pediatric Nf2-, Smarcb1-, And Lztr1-Related Schwannomatosis, Melissa R Perrino, Marjolijn C J Jongmans, Gail E Tomlinson, Mary-Louise C Greer, Sarah R Scollon, Sarah G Mitchell, Jordan R Hansford, Kris Ann P Schultz, Wendy K Kohlmann, Jennifer M Kalish, Suzanne P Macfarland, Anirban Das, Kara N Maxwell, Stefan M Pfister, Rosanna Weksberg, Orli Michaeli, Uri Tabori, Gina M Ney, Philip J Lupo, Jack J Brzezinski, Douglas R Stewart, Emma R Woodward, Christian P Kratz

Faculty, Staff and Students Publications

Schwannomatosis (SWN) is a distinct cancer predisposition syndrome caused by germline pathogenic variants in the genes NF2, SMARCB1, or LZTR1. There is a significant clinical overlap between these syndromes with the hallmark of increased risk for cranial, spinal, and peripheral schwannomas. Neurofibromatosis type 2 was recently renamed as NF2-related SWN and is the most common SWN syndrome, with increased risk for bilateral vestibular schwannomas, intradermal schwannomas, meningiomas, and less commonly, ependymoma. SMARCB1-related SWN is a familial SWN syndrome associated with peripheral and spinal schwannomas and an increased risk for meningiomas and malignant peripheral nerve sheath tumors, even in the absence …

A Hitchhiker’S Guide To Long-Read Genomic Analysis, Medhat Mahmoud, Daniel P Agustinho, Fritz J Sedlazeck

Faculty, Staff and Students Publications

Over the past decade, long-read sequencing has evolved into a pivotal technology for uncovering the hidden and complex regions of the genome. Significant cost efficiency, scalability, and accuracy advancements have driven this evolution. Concurrently, novel analytical methods have emerged to harness the full potential of long reads. These advancements have enabled milestones such as the first fully completed human genome, enhanced identification and understanding of complex genomic variants, and deeper insights into the interplay between epigenetics and genomic variation. This mini-review provides a comprehensive overview of the latest developments in long-read DNA sequencing analysis, encompassing reference-based and de novo assembly …

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, …

Spreading Depolarization And Seizures: End Of The Beginning, Or Beginning Of The End?, Isamu Aiba, Jeffrey L Noebels

Faculty, Staff and Students Publications

Like Janus, the Roman god of beginnings, transitions, and endings, spreading depolarizations (SDs) can be depicted with two faces: one looking backward, waving a symbolic farewell to the end of a cortical seizure; the other forward looking, opening a darker door for a fatal wave in the brainstem that ends life. There is good agreement on the distinct electrical nature of both events, but neither role is yet proven in patients. SD is a slow-moving wave of cellular depolarization that steadily silences neuronal networks and depresses EEG amplitude, whereas seizures represent fast, intermittent synchronization of neural networks with highly variable …

Global And Regional Disparities In Access To Specialist Sarcoma Services, Tomas Zamora, Eduardo Botello, Thomas Jenkins, Charlotte Jeys, Minna Laitinen, Ajay Puri, Lee Jeys, Boom Consensus Meeting Participants, Santiago Abad Repiso, Hesham Abdelbary, Alejandro Abiad Mejia, Ahmed Abood, Juan C Abril Martin, Adesegun Abudu, Ayman Abu Elhamd, Marthelena Acosta, Keisuke Ae, Manish Agarwal, Vivek Ajit Singh, Toru Akiyama, Ibrahim Alshaygy, Jose I Albergo, John Alexander, Patricio A Alfaro, Bugra Alpan, Jose Amaya-Valero, Megan Anderson, Dimosthenis Andreou, Lucas Annabell, Christopher Anthony, Ahmed Aoude, William Aston, Libe Asua Mentxaka, Christine Azzopardi, Thomas Baad-Hansen, Ismail T Badr, Francisco Baixauli-Garcia, Gavin Baker, Tessa Balach, Giacomo G Baldi, Janie Barry, Georges Basile, Stefano Bastoni, Mohammad H Basuki, Henrik Bauer, Lee Bayliss, Ricardo G Becker, Angad Bedi, Joseph Benevenia, Francisco Bengoa, Peter Bergh, Marko Bergovec, Nicholas Bernthal, Odion Binitie, David Boddie, Michele Boffano, Patricia Bonilla Huertas, Anna B Borgognoni, Rajesh Botchu, Richard A Boyle, Jos Bramer, Rahat Brar, Harriet Branford-White, Demien Broekhuis, Samuel E Broida, Tymoteusz Budny, Zachary D Burke, Jorge Cabrolier, Jose A Calvo-Haro, Jorge R Calvo-Tapies, Domenico A Campanacci, Rodrigo Cardoso, Richard Carey Smith, Pedro I Carvallo, Nicolas Casales Fresenga, Jose M Casanova, Oscar Ceballos, Juan L Cebrian Parra, Laura K Certain, Sara Chancon Cartaya, Chung M Chan, Yoon Joo Cho, Peter Choong, Yang-Guk Chung, David Ciechanowicz, David Clever, Sebastian Colina, Luis Consuegra, Cory Couch, Gillian Cribb, Carlos Cuervo, Laurence A Cusick, Solomon Dadia, Tanios Dagher, Dietmar Dammerer, Mark Davies, Nerys Davies, Luis P De La Rosa Martino, Francisco J De Santos De La Fuente, Marieke De Vaal, Claudia Deckers, Javier Delgado Obando, Shaneel Deo, Niklas Deventer, Claudia Di Bella, Gregory Domson, Davide M Donati, Desiree M Dorleijn, Jacques Du Toit, Debra Dunne, Rodolfo Duran Ciarrochi, Walid Ebeid, Elina Ekman, Ahmed M El Ghoneimy, Makoto Endo, Levent Eralp, Mahmoud Etaiwi, Scott Evans, Robin Evrard, Will Eward, Alberto Farese, Peter C Ferguson, Pedro F Ferreira Cardoso, Fabrice Fiorenza, Michael Flint, Hector Flores, Joao Freitas, Bruno Fuchs, Tomohiro Fujiwara, Philipp T Funovics, Marcos Galli Serra, Zakareya Gamie, Carlos Garces-Zarzalejo, Aaron Gazendam, Carsten Gebert, Jasper G Gerbers, Craig Gerrand, Ghaith Abou-Nouar, Michelle Ghert, Kanishka M Ghosh, Max Gibbons, Luis C Gomez-Mier, Jesus Gomez-Vallejo, Anne Gomez-Mascard, Marcos R Gonzalez, Fausto Gonzalez-Lizan, Georg Gosheger, Stuart Goudie, Krista Goulding, Stavros D Goumenos, Anthony Griffin, Ashish Gulia, Sanjay Gupta, Amit Gupta, Maurice Guzman, Mohammed Haitham, Jendrik Hardes, Francisco Hardoy, Yusuf Hasan, Georg Hauer, Helard Havard, Rex Haydon, John Healey, Nerea Hernandez Gonzalez, Adriana Hernandez-Lopez, Asle Hesla, Matthew Hess, Chindanai Hongsaprabhas, Francis Hornicek, Keith Hosking, Matthew T Houdek, Eleanor Houghton, Oluwaseyi K Idowu, Joseph Ippolito, Marc Isler, Shintaro Iwata, Jake Jagiello, Neil Jenkins, Tom Jeys, Luke Johnson, Andy Johnston, Min Wook Joo, Paul C Jutte, Kadri Kaldas, Amar Kamat, Sudhir Kannan, Bilal Kapanci, Zeeshan Khan, Hiroshi Kobayashi, Yehuda Kollender, Sebastian Koob, Daniel Kotrych, Vineet Kurisunkal, Richard Kyte, Jose M Lamo De Espinosa, Alexander L Lazarides, Louis-Romee Le Nail, Pawel Legosz, Burkhard Lehner, Andreas Leithner, Maryse Lejoly, Valerae O Lewis, Peng Lin, Francisco Linares, Santiago A Lozano-Calderon, Ashish Mahendra, Ferdiansyah Mahyudin, Fermin J Mandia Mancebo, Sara Martos Torrejon, Christian Marx, Eric Mascard, Jean-Camille Mattei, Louise Mccullough, Sam Mcmahon, Manuel R Medellin Rincon, Benjamin Miller, Shinji Miwa, Gustavo Molina Uribe, Bryan Moon, Thomas Hilton, Diego J Moriel Garcesco, Carol Morris, Guy Morris, Steward Morrison, Sophie Mottard, Marcio Moura, Linde Muster, Robert Nakayama, Prashant Narhari, Ana Navas, Prakash Nayak, Johannes Neugebauer, Erik T Newman, Jyrki Nieminen, Emmy Nyqvist, Lukas Nystrom, Sarah O'Reilly-Harbidge, Gary O'Toole, Vania Oliveira, André Olivier, Mohamed Omar, Eduardo J Ortiz-Cruz, Harzem Ozger, Korhan Ozkan, Elisa Pala, Emanuela Palmerini, Grant Pang, Panayiotis Papagelopoulos, Giovanni Paraliticci, Michael C Parry, Sam Patton, David Peake, Ana Peiro Ibanez, Israel Perez Munoz, Ganapathy R Perianayagam, Michael M Petersen, Joris Ploegmakers, Robin Pollock, Gerard Powell, Juan Pretell, Jan Puetzler, Faisal Qamar, Anand Raja, Raja B Rajasekaran, Dipak Ramkumar, R L Randall, Kenneth Rankin, Kevin A Raskin, Kumaran Rassppan, Lauris Repsa, Mickael Ropars, Peter Rose, Pietro Ruggieri, Wael Sadek, German Salcedo, Aasim Saleemi, Andrea Sambri, Hartej Sar, Roberto Scanferla, Thomas Schubert, Jan Schwarze, Guido Scoccianti, Ashley Scrimshire, Tetsuya Sekita, Ahmad Shehadeh, Ahmed Shoaib, Bhim Shreemal, Felix Shumelinsky, Geoffrey Siegel, Claudio Silveri, Robert Silverwood, Friedl Sinnaeve, Jerome Sison, Andrea Slade, Maria A Smolle, Franz Snyman, Scott Sommerville, Sahil Sood, Andre Spiguel, Hugo St-Yves, Eric L Staals, Silvia Stacchiotti, Nikolas Stavropoulos, Peter Steadman, Jonathan D Stevenson, Mikaela Sullivan, Gwen Sys, Bartlomiej Szostakowski, Angela Tamburini, Yuta Taniguchi, Thomas Temple, Christoph Theil, Joachim Thorkildsen, Meagan Tibbo, Roger Tillman, Yu Toda, Kaspar Tootsi, Ferran Torner-Rubies, Frank Traub, Ioannis Trikoupis, Panagiotis Tsagkozis, Kim Tsoi, Hiroyuki Tsuchiya, Veli-Matti Vainio, Antonio Valcarcel, Juan Valencia, Annelies Van Beeck, Michiel Van De Sande, Thomas Van Den Berghe, Ingrid Van Der Geest, Lizz Van Der Heijden, Robert Van Der Wal, Kirsten Van Langevelde, Gualter Vaz, Roberto Velez Villa, Floortje Verspoor, Koenraad Verstraete, Julia Visgauss, Oleg Vyrva, Hazem Wafa, Sebastian Walter, Wan F Wan Ismail, Edward Wang, Patrick Q Wang, David Warnock, Joel Werier, Wolfram Weschenfelder, Kwok-Chuen Wong, Marjan Wouthuyzen-Bakker, Jay Wunder, Indica Wysinghe, Norio Yamamoto, Zhaoming Ye, Seung-Jae Yoon, Suraya Zainul Abidin, Pierluca Zecchetto, Liuzhe Zhang, Juan P Zumarraga, Miguel A Clara-Altamirano

Faculty, Staff and Student Publications

Aims: Cancer care guidelines have been developed in many subspecialities, usually in advanced health systems. However, there are notable global disparities in healthcare access, which can impact sarcoma care. Unfortunately, there is a lack of global data on this subject. Our aim was to describe access to sarcoma care based on a comprehensive global survey among orthopaedic oncologists, and assess for global as well as regional differences.

Methods: A 25-question survey was emailed to the attendees of the 2024 Birmingham Orthopaedic Oncology Meeting and included questions about the respondents' training and practice, access to sarcoma centres, and specific items for …

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); …

The Zbtb24-Cdca7-Hells Axis Suppresses The Totipotent 2c-Like Reprogramming By Maintaining Dux Methylation And Repression, Dan Guo, Zeling Du, Youqi Liu, Meiqi Lin, Yue Lu, Swanand Hardikar, Yanna Xue, Jinghong Zhang, Taiping Chen, Jiameng Dan

Faculty, Staff and Student Publications

Two-cell-like cells (2CLCs), a rare population (∼0.5%) in mouse embryonic stem cell (mESC) cultures, are in a transient totipotent-like state resembling that of 2C-stage embryos, and their discovery and characterization have greatly facilitated the study of early developmental events, such as zygotic genome activation. However, the molecular determinants governing 2C-like reprogramming remain to be elucidated. Here, we show that ZBTB24, CDCA7, and HELLS, components of a molecular pathway that is involved in the pathogenesis of immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome, function as negative regulators of 2C-like reprogramming by maintaining DNA methylation of the Dux cluster, a master …

Cognitive Correlates Of Borderline Personality Disorder Features In Youth With Bipolar Spectrum Disorders And Bipolar Offspring, Alessio Simonetti, Sherin Kurian, Evelina Bernardi, Antonio Restaino, Francesca Bardi, Claudia Calderoni, Gabriele Sani, Jair C Soares, Kirti Saxena

Faculty, Staff and Student Publications

Background: Bipolar disorder (BD) and borderline personality disorder (BPD) share common cognitive impairments. These deficits are also shared by bipolar offspring (BD-OFF). Nevertheless, little is known regarding the association between cognitive impairments and BPD features in youth with BD and BD-OFF. Objectives: This study aimed to investigate the association between BPD features and cognitive impairments in youth with BD and BD-OFF.

Methods: Thirty-nine participants (7-17 years) with BD, 18 BD-OFF, and 50 healthy controls (HCs) were recruited. BPD features were assessed using the Borderline Personality Features Scale for Children (BPFS-C). Deficits in executive functions and affective processing were assessed using …

Heterozygous Hereditary Vitamin D-Dependent Rickets Type 2a (Vddr2a) In A Patient Presenting With Pseudoarthrosis, Risa Goldberg, Gunjan Umarji, Serge Jabbour

Division of Endocrinology, Diabetes and Metabolic Diseases Faculty Papers

This case report is centered on an atypical presentation of Hereditary Vitamin D-dependent Rickets 2A (VDDR2A), a rare disorder caused by defects in the gene encoding the vitamin D receptor (VDR). While this disorder is primarily autosomal recessive in inheritance, this case demonstrates that a single heterozygous variant in the VDR gene could be linked to both phenotypic and laboratory manifestations of this condition. To understand the pathogenesis of this condition, one must know the typical roles of vitamin D, calcium, and parathyroid hormone (PTH) in maintaining homeostasis in the body. This case report focuses on the underlying pathogenesis of …

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 …

An In Vivo Microscopy Dataset For The Characterization Of Leukocyte Death, Alain Pulfer, Diego Ulisse Pizzagalli, Miguel Palomino Segura, Nina Germic, Tommaso Virgilio, Mauro Di Pilato, Pau Carrillo Barbera, Elisa Palladino, Paola Antonello, Marcus Thelen, Hans-Uwe Simon, Rolf Krause, Santiago F Gonzalez

Faculty, Staff and Student Publications

Recent advancements in intravital microscopy have enabled the study of cell death in vivo under various experimental conditions, such as infection and cancer. However, the limited throughput of this technology, together with a lack of openly accessible datasets, affects the development of algorithms for the automatic detection and characterization of cell death, which in turn require the integration of extensive and curated datasets. To address these needs, we present a curated dataset of microscopy videos depicting the death of neutrophils, eosinophils, and dendritic cells, acquired in the spleen and in the lymph node of mice under inflammatory conditions. The dataset …

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 …

Mri-Based Digital Twins To Improve Treatment Response Of Breast Cancer By Optimizing Neoadjuvant Chemotherapy Regimens, Chengyue Wu, Ernesto A B F Lima, Casey E Stowers, Zhan Xu, Clinton Yam, Jong Bum Son, Jingfei Ma, Gaiane M Rauch, Thomas E Yankeelov

Faculty, Staff and Student Publications

We developed a practical framework to construct digital twins for predicting and optimizing triple-negative breast cancer (TNBC) response to neoadjuvant chemotherapy (NAC). This study employed 105 TNBC patients from the ARTEMIS trial (NCT02276443, registered on 10/21/2014) who received Adriamycin/Cytoxan (A/C)-Taxol (T). Digital twins were established by calibrating a biology-based mathematical model to patient-specific MRI data, which accurately predicted pathological complete response (pCR) with an AUC of 0.82. We then used each patient's twin to theoretically optimize outcome by identifying their optimal A/C-T schedule from 128 options. The patient-specifically optimized treatment yielded a significant improvement in pCR rate of 20.95-24.76%. Retrospective …

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 …

Breaking The Synaptic Vesicle Cycle: Mechanistic Insights Into Presynaptic Dysfunctions In Epilepsy, Kevin Jiang, Lu-Tang Yang, Mingshan Xue

Duncan NRI Faculty and Staff Publications

Synaptic dysfunction is a hallmark of many neurological disorders including epilepsy. An increasing number of epilepsy-causing pathogenic variants are being identified in genes encoding presynaptic proteins that affect every step of the synaptic vesicle cycle, from vesicle loading, tethering, docking, priming, calcium sensing, fusing, to recycling. These different molecular dysfunctions result in converging impairment of presynaptic neurotransmitter release, yet lead to diverse epileptic disorders. This review focuses on representative monogenic epileptic disorders caused by pathogenic variants of key presynaptic proteins involved in different stages of the synaptic vesicle cycle: SYN1 (vesicle pool regulation), STXBP1 (vesicle docking, priming, and fusion), and …

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 …