Medical Specialties Commons^™

Integrated Analysis Of Molecular And Clinical Features Associated With Overall Survival In Melanoma Patients With Brain Metastasis, Swaminathan Kumar, Meredith S Pelster, Merve Hasanov, Renato A Guerrieri, Courtney W Hudgens, Debora A Ledesma, Fuchenchu Wang, Grant M Fischer, Julie M Simon, Lauren E Haydu, Kalman V Katlowitz, Y N Vashisht Gopal, Jennifer L Mcquade, Lawrence N Kwong, Jason T Huse, Alexander J Lazar, Michael T Tetzlaff, Jeffrey E Gershenwald, Aron Y Joon, Ken Chen, Ziyi Li, Prahlad T Ram, Sherise D Ferguson, Michael A Davies

Faculty, Staff and Student Publications

Melanoma brain metastases (MBMs) are diagnosed in up to 60% of metastatic melanoma patients. Previous studies have identified clinical factors that correlate with overall survival (OS) after MBM diagnosis. However, molecular and immune features associated with OS are poorly understood. An improved understanding of the molecular and immune correlates of OS could provide insights into MBM patient outcomes and guide therapeutic development. Thus, we analyzed clinical features and outcomes of 74 melanoma patients who underwent surgical resection (via craniotomy) between 1991 and 2015 at our institution with RNA-seq data generated from their MBMs. The median post-operative OS was 8.6 months …

Single-Cell Analyses Reveal A Functionally Heterogeneous Exhausted Cd8+ T-Cell Subpopulation That Is Correlated With Response To Checkpoint Therapy In Melanoma, Kelly M Mahuron, Osmaan Shahid, Prachi Sao, Clinton Wu, Alexandra M Haugh, Laura A Huppert, Lauren S Levine, Margaret M Lowe, Michael Alvarado, Markee Micu, Katy K Tsai, Melissa Chow, Meromit Singer, Jason M Schenkel, Arlene H Sharpe, Michael D Rosenblum, Kristen E Pauken, Adil I Daud

Faculty, Staff and Student Publications

PD-1 pathway inhibitors have revolutionized cancer therapy. However, most patients do not durably benefit, highlighting the need for biomarkers to stratify patients as responders or nonresponders. Although CD8+ tumor-infiltrating lymphocytes (TIL) have been associated with immune checkpoint therapy response, there is no consensus on which CD8+ TIL subpopulations have the most prognostic value. Preclinical studies have focused on progenitor-like exhausted CD8+ T cells (TPEX) because TPEX proliferate more in response to PD-1 inhibitors than other exhausted T-cell (TEX) subpopulations. However, immune checkpoint inhibitor treatment drives TPEX differentiation into other TEX populations that can mediate antitumor immunity. These data complicate the …

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 …

Region-Specific Roles Of Oviductal Motile Cilia In Oocyte/Embryo Transport And Fertility†, Deirdre M Scully, Tian Xia, Guzel R Musina, Michaela A Mccown, Kohei Umezu, Bonnie K Kircher, Richard R Behringer, Irina V Larina

Faculty, Staff and Students Publications

The physiological and clinical importance of motile cilia in reproduction is well recognized; however, the specific role they play in transport through the oviduct and how ciliopathies lead to subfertility and infertility are still unclear. The contribution of cilia beating, fluid flow, and smooth muscle contraction to overall progressive transport within the oviduct remains under debate. Therefore, we investigated the role of cilia in the oviduct transport of preimplantation eggs/embryos using a combination of genetic and advanced imaging approaches. We show that the region of the oviduct where cumulus-oocyte complex circling occurs, around the time of fertilization, is correlated with …

Clinical Decision-Making And Artificial Intelligence: The Role Of Large Language Models In Medicine, Richa Bhasin, Wassim El-Sayed, Kassim Salami, Mura Abdul-Nabi, Ahmed Elashmawy, M. Ellis Jaruzel Ii

Clinical Research in Practice: The Journal of Team Hippocrates

A clinical decision report using:

Goh E, Gallo R, Hom J, et al. Large Language Model Influence on Diagnostic Reasoning: A Randomized Clinical Trial. JAMA Netw Open. 2024;7(10):e2440969. https://doi.org/10.1001/jamanetworkopen.2024.40969

to explore the role of artificial intelligence in clinical settings.

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

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); …

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 …

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 …

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 …

Differential Antibody Response To Ebv Proteome Following Ebvst Immunotherapy In Ebv-Associated Lymphomas, Yomani D Sarathkumara, Nathan W Van Bibber, Zhiwei Liu, Helen E Heslop, Rayne H Rouce, Anna E Coghill, Cliona M Rooney, Carla Proietti, Denise L Doolan

Faculty, Staff and Students Publications

Epstein-Barr virus (EBV) is associated with a diverse range of lymphomas. EBV-specific T-cell (EBVST) infusions have shown promise in safety and clinical effectiveness in treating EBV-associated lymphomas; however, not all patients respond to T-cell immunotherapies. To identify EBV antigen–specific antibody responses associated with clinical outcomes, we comprehensively characterized antibody responses to the complete EBV proteome using a custom protein microarray in 56 patients with EBV-associated lymphoma who received EBVST infusions in phase 1 clinical trials. Responders (nonprogressors) and nonresponders (progressors) had distinct antibody profiles against EBV. Twenty-five immunoglobulin G (IgG) antibodies were significantly elevated in higher levels in nonresponders than …

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 …

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 …

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 …

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 …

Computational Sensitivity Evaluation Of Ultrasound Neuromodulation Resolution To Brain Tissue Sound Speed With Robust Beamforming, Boqiang Fan, Wayne Goodman, Sameer A Sheth, Richard R Bouchard, Behnaam Aazhang

Faculty, Staff and Student Publications

Low-intensity focused ultrasound (LIFU) neuromodulation requires precise targeting and high resolution enabled by phased array transducers and beamforming. However, focusing optimization usually relies on phantom measurements or simulations with inaccurate acoustic properties to degrade neuromodulation resolution. Therefore, this work analyzes the sensitivity of neuromodulation resolution, measured by off-target activation area (OTAA), to brain tissue sound speed. A Robust Optimal Resolution (ROR) beamforming method is proposed to minimize the worst-case OTAA with restricted sound speed inaccuracy and propagation information estimated with deviated sound speed. The propagation estimation model utilizes equivalent source method (ESM) to map sound field between different acoustic parameter …

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 …

Ven In Combination With 10-Day Dec In Newly Diagnosed Elderly Or Relapsed/Refractory Acute Myeloid Leukemia, And High-Risk Myelodysplastic Syndrome: Long Term Follow-Up Of A Phase 2 Trial, Mahesh Swaminathan, Courtney D Dinardo, Abhishek Maiti, Naveen Pemmaraju, Maro Ohanian, Navel G Daver, Guillermo Garcia-Manero, Ghayas C Issa, Gautam Borthakur, Farhad Ravandi, Guillermo Montalban-Bravo, Tapan M Kadia, Yesid Alvarado, Elias J Jabbour, Nicholas J Short, William G Wierda, Nitin Jain, Steven M Kornblau, Lucia Masarova, Sherry A Pierce, Wei Qiao, Jing Ning, Hagop Kantarjian, Marina Y Konopleva

Faculty, Staff and Student Publications

No abstract provided.

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 …

Prdm1 Is A Key Regulator Of The Nkt-Cell Central Memory Program And Effector Function, Gengwen Tian, Gabriel A Barragan, Hangjin Yu, Claudia Martinez-Amador, Akshaya Adaikkalavan, Xavier Rios, Linjie Guo, Janice M Drabek, Osmay Pardias, Xin Xu, Antonino Montalbano, Chunchao Zhang, Yanchuan Li, Amy N Courtney, Erica J Di Pierro, Leonid S Metelitsa

Faculty, Staff and Students Publications

Natural killer T cells (NKTs) are a promising platform for cancer immunotherapy, but few genes involved in the regulation of NKT therapeutic activity have been identified. To find regulators of NKT functional fitness, we developed a CRISPR/Cas9-based mutagenesis screen that uses a guide RNA (gRNA) library targeting 1,118 immune-related genes. Unmodified NKTs and NKTs expressing a GD2-specific chimeric antigen receptor (GD2.CAR) were transduced with the gRNA library and exposed to CD1d+ leukemia or CD1d-GD2+ neuroblastoma cells, respectively, over six challenge cycles in vitro. Quantification of gRNA abundance revealed enrichment of PRDM1-specific gRNAs in both NKTs and GD2.CAR NKTs, a result …

Dysregulation Of Mirna Expression And Excitation In Mef2c Autism Patient Hipsc-Neurons And Cerebral Organoids, Dorit Trudler, Swagata Ghatak, Michael Bula, James Parker, Maria Talantova, Melissa Luevanos, Sergio Labra, Titas Grabauskas, Sarah Moore Noveral, Mayu Teranaka, Emily Schahrer, Nima Dolatabadi, Clare Bakker, Kevin Lopez, Abdullah Sultan, Parth Patel, Agnes Chan, Yongwook Choi, Riki Kawaguchi, Pawel Stankiewicz, Ivan Garcia-Bassets, Piotr Kozbial, Michael G Rosenfeld, Nobuki Nakanishi, Daniel H Geschwind, Shing Fai Chan, Wei Lin, Nicholas J Schork, Rajesh Ambasudhan, Stuart A Lipton

Faculty, Staff and Students Publications

MEF2C is a critical transcription factor in neurodevelopment, whose loss-of-function mutation in humans results in MEF2C haploinsufficiency syndrome (MHS), a severe form of autism spectrum disorder (ASD)/intellectual disability (ID). Despite prior animal studies of MEF2C heterozygosity to mimic MHS, MHS-specific mutations have not been investigated previously, particularly in a human context as hiPSCs afford. Here, for the first time, we use patient hiPSC-derived cerebrocortical neurons and cerebral organoids to characterize MHS deficits. Unexpectedly, we found that decreased neurogenesis was accompanied by activation of a micro-(mi)RNA-mediated gliogenesis pathway. We also demonstrate network-level hyperexcitability in MHS neurons, as evidenced by excessive synaptic …

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 …