Digital Commons Network^™

An Intranasally Administered Igm Protects Against Antigenically Distinct Subtypes Of Influenza A Viruses, Ashwin Kumar Ramesh, Jwala Priyadarsini Sivaccumar, Xiaohua Ye, Luona Yang, Hailong Guo, Chen-Ni Chin, Sha Ha, John W Shiver, William R Strohl, Yan Xu, Haijuan Du, Tongqing Zhou, Ningyan Zhang, Kai Xu, Xinli Liu, Tong-Ming Fu, Zhiqiang An

Faculty, Staff and Student Publications

Engineering broadly neutralizing monoclonal antibodies (mAbs) targeting the hemagglutinin (HA) of Influenza A virus (IAV) is a promising approach for intervention of seasonal flu. However, HA plasticity often leads to resistant strains that compromise mAb potency as bivalent IgGs. Here we hypothesize that multimerization of anti-IAV antibodies as IgMs can enhance coverage and neutralization potency. Here, we construct 18 IgM antibodies from known broadly neutralizing IgGs targeting different IAV HA epitopes and evaluate their breadth and potency of neutralization against distinct H1N1 and H3N2 IAVs. The IgM version of receptor binding site-specific IgG F045-092 shows increased breadth and antiviral potency …

The Potential Of Brain Organoids In Addressing The Heterogeneity Of Synucleinopathies, Xiao-Jun Diao, Claudio Soto, Fei Wang, Yu Wang, Yun-Cheng Wu, Abhisek Mukherjee

Faculty, Staff and Student Publications

Synucleinopathies are a group of diseases characterized by neuronal and glial accumulation of α-synuclein (aSyn) linked with different clinical presentations, including Parkinson's disease (PD), Parkinson's disease with dementia (PDD), Dementia with Lewy Bodies (DLB) and Multiple system atrophy (MSA). Interestingly, the structure of the aSyn aggregates can vary across different synucleinopathies. Currently, it is unclear how the aSyn protein can aggregate into diverse structures and affect distinct cell types and various brain regions, leading to different clinical symptoms. Recent advances in induced pluripotent stem cells (iPSCs)-based brain organoids (BOs) technology provide an unprecedented opportunity to define the etiology of synucleinopathies …

Investigative Needle Core Biopsies Support Multimodal Deep-Data Generation In Glioblastoma, Kenny K H Yu, Sreyashi Basu, Gerard Baquer, Ryuhjin Ahn, Jennifer Gantchev, Sonali Jindal, Michael S Regan, Zaki Abou-Mrad, Michael C Prabhu, Marc J Williams, Alicia D D'Souza, Seth W Malinowski, Kelsey Hopland, Yuval Elhanati, Sylwia A Stopka, Alexei Stortchevoi, Charles Couturier, Zhong He, Jingjing Sun, Yulong Chen, Alexsandra B Espejo, Kin Hoe Chow, Smitha Yerrum, Pei-Lun Kao, Brittany Parker Kerrigan, Lisa Norberg, Douglas Nielsen, Vinay K Puduvalli, Jason Huse, Rameen Beroukhim, Betty Y S Kim, Sangeeta Goswami, Adrienne Boire, Sarah Frisken, Michael J Cima, Matthias Holdhoff, Calixto-Hope G Lucas, Chetan Bettegowda, Stuart S Levine, Tejus A Bale, Cameron Brennan, David A Reardon, Frederick F Lang, E Antonio Chiocca, Keith L Ligon, Forest M White, Padmanee Sharma, Viviane Tabar, Nathalie Y R Agar

Faculty, Staff and Student Publications

Glioblastoma (GBM) is an aggressive primary brain cancer with few effective therapies. Stereotactic needle biopsies are routinely used for diagnosis; however, the feasibility and utility of investigative biopsies to monitor treatment response remains ill-defined. Here, we demonstrate the depth of data generation possible from routine stereotactic needle core biopsies and perform highly resolved multi-omics analyses, including single-cell RNA sequencing, spatial transcriptomics, metabolomics, proteomics, phosphoproteomics, T-cell clonotype analysis, and MHC Class I immunopeptidomics on standard biopsy tissue obtained intra-operatively. We also examine biopsies taken from different locations and provide a framework for measuring spatial and genomic heterogeneity. Finally, we investigate the …

Building A Pre-Surgical Multiparametric-Mri-Based Morphologic, Qualitative, Semiquantitative, First And High-Order Radiomic Predictive Treatment Response Model For Undifferentiated Pleomorphic Sarcoma To Replace Recist, Raul F Valenzuela, Elvis Duran-Sierra, Mathew Antony, Behrang Amini, Sam Lo, Keila E Torres, Robert S Benjamin, Jingfei Ma, Ken-Pin Hwang, R Jason Stafford, Dejka Araujo, Andrew J Bishop, Ravin Ratan, Wei-Lien Wang, Jossue Espinoza, Pia V Valenzuela, Chengyue Wu, John E Madewell, William A Murphy, Colleen M Costelloe

Faculty, Staff and Student Publications

Background: Undifferentiated pleomorphic sarcoma (UPS) is the largest subgroup of soft-tissue sarcomas. It demonstrates post-therapeutic hemosiderin deposition, granulation tissue formation, fibrosis, and calcification. Our research aims to establish the multiparametric MRI (mp-MRI) value for predicting UPS treatment response.

Methods: An IRB-approved retrospective study included 33 extremity UPS patients with pre-operative mp-MRI, including diffusion-weighted imaging (DWI), contrast-enhanced susceptibility-weighted imaging (CE-SWI), and perfusion-weighted imaging with dynamic contrast-enhancement (PWI/DCE), and surgical resection between February 2021 and May 2023. Lesions were visually classified on CE-SWI into one of 6 morphology patterns. On PWI/DCE, lesions were classified into one of 6 patterns, and time-intensity curves …

Acute Brcaness Induction And Ar Pathway Blockage Through Cdk12/7/9 Degradation Enhances Parp Inhibitor Sensitivity In Prostate Cancer, Fu Gui, Baishan Jiang, Jie Jiang, Zhixiang He, Takuya Tsujino, Tomoaki Takai, Seiji Arai, Celine Pana, Jens Köllermann, Gary Andrew Bradshaw, Robyn Eisert, Marian Kalocsay, Anne Fassl, Steven P Balk, Adam S Kibel, Li Jia

Faculty, Staff and Student Publications

Current treatments for advanced prostate cancer (PCa) primarily target the androgen receptor (AR) pathway. However, the emergence of castration-resistant prostate cancer (CRPC) and resistance to AR pathway inhibitors (APPIs) remains ongoing challenges. Here, we present BSJ-5-63, a proteolysis-targeting chimera (PROTAC) targeting cyclin-dependent kinases (CDKs) CDK12, CDK7, and CDK9, offering a multipronged approach to CRPC therapy. BSJ-5-63 degrades CDK12, diminishing BRCA1 and BRCA2 expression and inducing a sustained "BRCAness" state. This sensitizes cancer cells to PARP inhibitors (PARPis) regardless of their homologous recombination repair (HRR) status. Furthermore, CDK7 and CDK9 degradation attenuates AR signaling, enhancing its therapeutic efficacy. Preclinical studies, including …

Idh Status Dictates Ohsv Mediated Metabolic Reprogramming Affecting Anti-Tumor Immunity, Upasana Sahu, Matthew P Mullarkey, Sara A Murphy, Joshua C Anderson, Vasanta Putluri, Abu Hena Mostafa Kamal, Jun Hyoung Park, Tae Jin Lee, Alexander L Ling, Benny A Kaipparettu, Ashok Sharma, Nagireddy Putluri, Pamela L Wenzel, Christopher D Willey, E Antonio Chiocca, James M Markert, Balveen Kaur

Faculty, Staff and Student Publications

Identification of isocitrate dehydrogenase (IDH) mutations has uncovered the crucial role of metabolism in gliomagenesis. Oncolytic herpes virus (oHSV) initiates direct tumor debulking by tumor lysis and activates anti-tumor immunity, however, little is known about the role of glioma metabolism in determining oHSV efficacy. Here we identify that oHSV rewires central carbon metabolism increasing glucose utilization towards oxidative phosphorylation and shuttling glutamine towards reductive carboxylation in IDH wildtype glioma. The switch in metabolism results in increased lipid synthesis and cellular ROS. PKC induces ACSL4 in oHSV treated cells leading to lipid peroxidation and ferroptosis. Ferroptosis is critical to launch an …

Impact Of Antidiabetic Medication Type On A New Episode Of Depression: A Retrospective Cohort Study In Texas, Usa, Lin-Na Chou, Mukaila A Raji, Holly M Holmes, Yong-Fang Kuo

Faculty, Staff and Student Publications

Objectives: To examine the associations between antidiabetic medication type and a new episode of depression using 100% Texas Medicare database during 2009 and 2018.

Design: A retrospective cohort study.

Setting: A population-based study using the Texas Medicare data.

Interventions: 11 common antihyperglycaemic medication types, alone and in combinations: metformin-only, five non-metformin-containing regimens (dipeptidyl peptidase-4 inhibitor (DPP4i) only, sulfonylureas (SU) only, thiazolidinediones (TZD) only, SU/DPP4i and SU/TZD) and five metformin-containing combination treatments (metformin/DPP4i, metformin/SU, metformin/TZD, metformin/SU/DPP4i and metformin/SU/TZD).

Participants: This study included 59 057 type 2 diabetes (T2D) patients from a cohort of Texas Medicare beneficiaries who were aged ≥66 years, …

Retrospective Analysis Of Cement Extravasation Rates In Vertebroplasty, Kyphoplasty, And Bone Tumor Radiofrequency Ablation, Soun Sheen, Prit Hasan, Xiaowen Sun, Jian Wang, Claudio Tatsui, Kent Nouri, Saba Javed

Faculty, Staff and Student Publications

Background: Percutaneous vertebral augmentation techniques, including vertebroplasty, kyphoplasty, and bone tumor radiofrequency ablation (BT-RFA), are commonly used to treat painful vertebral compression fractures (VCFs). While generally safe and effective, they carry risks, including cement extravasation, which can lead to pulmonary embolism or spinal cord compression. This study aims to compare the rate of cement extravasation across different vertebral augmentation techniques and identify potential risk factors.

Methods: A retrospective cohort study was conducted at a comprehensive cancer center on 1002 procedure encounters in 888 patients who underwent vertebral augmentation for painful VCFs. Data were collected on patient demographics, fracture pathology, procedure …

Tobacco Smoking Functional Networks: A Whole-Brain Connectome Analysis In 24 539 Individuals, Yezhi Pan, Chuan Bi, Zhenyao Ye, Hwiyoung Lee, Jiaao Yu, Luba Yammine, Tianzhou Ma, Peter Kochunov, L Elliot Hong, Shuo Chen

Faculty, Staff and Student Publications

Introduction: Nicotine addiction, a multifaceted neuropsychiatric disorder, profoundly impacts brain functions through interactions with neural pathways. Despite its significance, the impact of tobacco smoking on the whole-brain functional connectome remains largely unexplored.

Aims and methods: We conducted a whole-brain analysis on 24 539 adults aged 40 and above from the United Kingdom Biobank cohort. Subjects were categorized into individuals who use nicotine and those who do not use nicotine based on current and chronic tobacco smoking information. Functional connectivity was assessed using resting-state functional magnetic resonance imaging. We employed a network analysis method to assess the systematic effects of tobacco …

Can The Discovery Of High-Impact Diagnostics Be Improved By Matching The Sampling Rate Of Clinical Diagnostics To The Frequency Domain Of Diagnostic Information?, Steven W Millward, Peng Wei, David Piwnica-Worms, Seth T Gammon

Faculty, Staff and Student Publications

Over the past 30 years, academic and industrial research investigators have developed molecular reporters to visualize cell death in complex biological systems. In parallel, clinical researchers, chemists, biochemists, and molecular biologists have endeavored to translate these molecular tools into clinical imaging agents. Despite these efforts, there are no clinically approved imaging methodologies with which to image cell death consistently and quantitatively. One reason may reside in the intrinsic mismatch between the sampling frequency of translational molecular imaging and the biochemical kinetics that define cell death. Beyond cell death imaging, many active research programs are now attempting to create translational diagnostic …

Rnase1-Driven Alk-Activation Is An Oncogenic Driver And Therapeutic Target In Non-Small Cell Lung Cancer, Zhengyu Zha, Chunxiao Liu, Meisi Yan, Cong Chen, Cheng Yu, Yaohui Chen, Chenhao Zhou, Lu Li, Yi-Chuan Li, Hiro Yamaguchi, Leiguang Ye, Tong Liu, Ying-Nai Wang, Heng-Huan Lee, Wen-Hao Yang, Li-Chuan Chan, Baozhen Ke, Jennifer L Hsu, Lieming Ding, Dong Ji, Peng Pan, Yiran Meng, Yue Pu, Lunxu Liu, Mien-Chie Hung

Faculty, Staff and Student Publications

Targeted therapy has achieved significant success in the treatment of non-small cell lung cancer (NSCLC), particularly in patients harboring common oncogenic driver mutations such as EGFR, KRAS, and ALK rearrangement. However, ~35-50% of NSCLC patients without tyrosine kinase mutation or rearrangement (non-mutated) cannot benefit from these targeted treatments, highlighting the urgent need for novel therapeutic strategies for this patient population. In this study, we report a non-canonical role of human secretory ribonuclease 1 (RNase1), which binds to and activates wild-type ALK in lung cancer cells, thereby triggering its downstream signaling pathway. RNase1-driven ALK-activation (RDAA) cells exhibit enhanced cell proliferation, migration, …

Enriched Pathways In Gut Microbiome Predict Response To Immune Checkpoint Inhibitor Treatment Across Demographic Regions And Various Cancer Types, Xunhui Cai, Jennifer Y Cho, Lijun Chen, Yufeng Liu, Fenghu Ji, Katia Salgado, Siyi Ge, Dehua Yang, Hui Yu, Jianbo Shao, P Andrew Futreal, Boris Sepesi, Don Gibbons, Yaobing Chen, Guoping Wang, Chao Cheng, Meng Wu, Jianjun Zhang, Ansel Hsiao, Tian Xia

Faculty, Staff and Student Publications

Understanding the effect of gut microbiota function on immune checkpoint inhibitor (ICI) responses is urgently needed. Here, we integrated 821 fecal metagenomes from 12 datasets to identify differentially abundant genes and construct random forest models to predict ICI response. Gene markers demonstrated excellent predictive performance, with an average area under the curve (AUC) of 0.810. Pathway analyses revealed that quorum sensing (QS), ABC transporters, flagellar assembly, and amino acid biosynthesis pathways were enriched between responders (R) and non-responders (NRs) across 12 datasets. Furthermore,

G-Protein-Coupled Estrogen Receptor 1 And Pregnancy Confer Protection Against Hypertension In Older Females, Ravneet Singh, Supaporn Kulthinee, Victoria L Nasci, Elvis A Akwo, Chibundu Juliet Umunna, Rawan N Almutlaq, Oleh M Pochynyuk, Cassianne Robinson-Cohen, Eman Y Gohar

Faculty, Staff and Student Publications

No abstract provided.

Vacuum Erectile Devices For Erectile Dysfunction: Recommendations From The 5th International Consultation On Sexual Medicine, Run Wang, Francisco E Martins, David Ralph, Georgios Hatzichristodoulou, Daniar Osmonov, Justin Parker, Sung Hun Sean Park, Ignacio Moncada, Carlo Bettocchi, Ricardo Munarriz, Tobias Köhler

Faculty, Staff and Student Publications

Introduction: Vacuum erectile device (VED) is 1 of the main approved therapies for erectile dysfunction (ED). The introduction of phosphodiesterase type 5 inhibitor (PDE5i) for ED significantly changed the roles of VED in contemporary sexual medicine.

Objective: To provide updated clinical evidence to inform health care providers on best practices with VED.

Methods: A consensus panel was held with leading sexual medicine experts during the 5th International Consultation on Sexual Medicine (ICSM). Relevant peer-reviewed literature was reviewed with focus on research from the last 10 years, but not limited to the last 10 years. The expert panel generated consensus statements …

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 …

Whole Genome Sequencing Analysis Of Body Mass Index Identifies Novel African Ancestry-Specific Risk Allele, Xinruo Zhang, Jennifer A Brody, Mariaelisa Graff, Heather M Highland, Nathalie Chami, Hanfei Xu, Zhe Wang, Kendra R Ferrier, Geetha Chittoor, Navya Shilpa Josyula, Mariah Meyer, Shreyash Gupta, Xihao Li, Zilin Li, Matthew A Allison, Diane M Becker, Lawrence F Bielak, Joshua C Bis, Meher Preethi Boorgula, Donald W Bowden, Jai G Broome, Erin J Buth, Christopher S Carlson, Kyong-Mi Chang, Sameer Chavan, Yen-Feng Chiu, Lee-Ming Chuang, Matthew P Conomos, Dawn L Demeo, Mengmeng Du, Ravindranath Duggirala, Celeste Eng, Alison E Fohner, Barry I Freedman, Melanie E Garrett, Xiuqing Guo, Chris Haiman, Benjamin D Heavner, Bertha Hidalgo, James E Hixson, Yuk-Lam Ho, Brian D Hobbs, Donglei Hu, Qin Hui, Chii-Min Hwu, Rebecca D Jackson, Deepti Jain, Rita R Kalyani, Sharon L R Kardia, Tanika N Kelly, Ethan M Lange, Michael Lenoir, Changwei Li, Loic Le Marchand, Merry-Lynn N Mcdonald, Caitlin P Mchugh, Alanna C Morrison, Take Naseri, Jeffrey O'Connell, Christopher J O'Donnell, Nicholette D Palmer, James S Pankow, James A Perry, Ulrike Peters, Michael H Preuss, D C Rao, Elizabeth A Regan, Sefuiva M Reupena, Dan M Roden, Jose Rodriguez-Santana, Colleen M Sitlani, Jennifer A Smith, Hemant K Tiwari, Ramachandran S Vasan, Zeyuan Wang, Daniel E Weeks, Jennifer Wessel, Kerri L Wiggins, Lynne R Wilkens, Peter W F Wilson, Lisa R Yanek, Zachary T Yoneda, Wei Zhao, Sebastian Zöllner, Donna K Arnett, Allison E Ashley-Koch, Kathleen C Barnes, John Blangero, Eric Boerwinkle, Esteban G Burchard, April P Carson, Daniel I Chasman, Yii-Der Ida Chen, Joanne E Curran, Myriam Fornage, Victor R Gordeuk, Jiang He, Susan R Heckbert, Lifang Hou, Marguerite R Irvin, Charles Kooperberg, Ryan L Minster, Braxton D Mitchell, Mehdi Nouraie, Bruce M Psaty, Laura M Raffield, Alexander P Reiner, Stephen S Rich, Jerome I Rotter, M Benjamin Shoemaker, Nicholas L Smith, Kent D Taylor, Marilyn J Telen, Scott T Weiss, Yingze Zhang, Nancy Heard-Costa, Yan V Sun, Xihong Lin, L Adrienne Cupples, Leslie A Lange, Ching-Ti Liu, Ruth J F Loos, Kari E North, Anne E Justice

Faculty, Staff and Student Publications

Obesity is a major public health crisis associated with high mortality rates. Previous genome-wide association studies (GWAS) investigating body mass index (BMI) have largely relied on imputed data from European individuals. This study leveraged whole-genome sequencing (WGS) data from 88,873 participants from the Trans-Omics for Precision Medicine (TOPMed) Program, of which 51% were of non-European population groups. We discovered 18 BMI-associated signals (P <  5 × 10

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

Effects Of Metformin Use On Aneurysmal Subarachnoid Hemorrhage Outcomes, Angel Bueno, Andrea Becerril-Gaitan, Collins Mokua, Kristina Ramirez-Garcia, Justin Nguyen, Faris Shaker, Tien Nguyen, Antonio Dono, Spiros Blackburn, Peng Roc Chen, Mark Dannenbaum, H Alex Choi, Arthur L Day, Jacques J Morcos, Ching-Jen Chen

Faculty, Staff and Student Publications

Background: Metformin is widely prescribed and has neuroprotective effects in animals, but its impact on brain injury after aneurysmal subarachnoid hemorrhage (aSAH) in humans is unclear.

Methods: This single-center retrospective review assessed patients with aSAH from 2009 to 2023, categorizing them based on pre-admission metformin use. The primary outcome was delayed cerebral ischemia (DCI), while secondary outcomes included in-hospital mortality, rebleeding, angiographic cerebral vasospasm (CVS), and favorable modified Rankin Scale (mRS) scores at discharge and the 3-month follow-up. Outcomes were analyzed using logistic regression. Sensitivity analysis was performed after excluding patients receiving comfort care.

Results: A total of 900 patients …

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 …

Association Of Clonal Hematopoiesis Of Indeterminate Potential With Cardiovascular Events In Patients With Ckd, Yang Pan, Caitlyn Vlasschaert, Varun Rao, Elvis A Akwo, James E Hixson, Md Mesbah Uddin, Zhi Yu, Do-Kyun Kim, Alexander Bick, Bryan Kestenbaum, Michael Chong, Guillaume Paré, Michael Rauh, Adeera Levin, James P Lash, Manjula Kurella Tamura, Debbie L Cohen, Jiang He, Lee Hamm, Rajat Deo, Zeenat Bhat, Panduranga Rao, Dawei Xie, Pradeep Natarajan, Tanika N Kelly, Cassianne Robinson-Cohen, Matthew B Lanktree

Faculty, Staff and Student Publications

Key Points:

1. In patients with CKD, non-DNMT3A clonal hematopoiesis of indeterminate potential (CHIP) was associated with higher risk of cardiovascular events.

2. There was no significant difference in the CHIP–cardiovascular disease association based on baseline eGFR, diabetes status, or race.

3. The protective effect of IL6R p.Asp358Ala on non-DNMT3A CHIP cardiovascular risk was similar to the general population.

Background: Patients with CKD are at higher risk of cardiovascular disease. Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with cardiovascular disease in the general population, with a causal role observed in animal models. In the general population, the effect of …

Cell Type-Specific Multi-Omics Analysis Of Cocaine Use Disorder In The Human Caudate Nucleus, Lea Zillich, Annasara Artioli, Veronika Pohořalá, Eric Zillich, Laura Stertz, Hanna Belschner, Ammar Jabali, Josef Frank, Fabian Streit, Diana Avetyan, Maja P Völker, Svenja Müller, Anita C Hansson, Thomas D Meyer, Marcella Rietschel, Julia Ladewig, Rainer Spanagel, Ana M M Oliveira, Consuelo Walss-Bass, Rick E Bernardi, Philipp Koch, Stephanie H Witt

Faculty, Staff and Student Publications

Structural and functional alterations in the brain's reward circuitry are present in cocaine use disorder (CocUD), but their molecular underpinnings remain unclear. To investigate these mechanisms, we performed single-nuclei multiome profiling on postmortem caudate nucleus tissue from six individuals with CocUD and eight controls. We profiled 30,030 nuclei, identifying 13 cell types including D1- and D2-medium spiny neurons (MSNs) and glial cells. We observed 1485 differentially regulated genes and 10,342 differentially accessible peaks, with alterations in MSNs and astrocytes related to neurotransmitter activity and synapse organization. Gene regulatory network analysis identified transcription factors including ZEB1 as exhibiting distinct CocUD-specific subclusters, …

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 …

Gpat4 Sustains Endoplasmic Reticulum Homeostasis In Endocardial Cells And Safeguards Heart Development, Tianyang Zhao, Kuipei Jin, Xiaodong Wang, Xiong Su, Youjun Wang, Mingming Gao, Wen Luo, Hongyuan Yang, Zhongzhou Yang

Faculty, Staff and Student Publications

The endocardium plays a pivotal role in governing myocardial development, and understanding the intrinsic regulatory insights will help apprehend pathological cardiomyopathy. Glycerol-3-phosphate acyltransferase 4 (GPAT4) is an endoplasmic reticulum (ER) membrane anchored protein. While the role of GPAT4 in glycerophospholipid biosynthesis is well established, its function in the ER is less explored. Here, we generate Gpat4 global and tissue-specific knockout mice and identify the essential role of GPAT4 in endocardial development. Deficiency of GPAT4 provokes endocardial ER stress response and enhances ER-mitochondrial (ER-mito) communications, leading to mitochondrial DNA (mtDNA) escape. As a result, the cGAS-STING pathway is triggered to stimulate …

Alterations In Dna Methylation, Proteomic, And Metabolomic Profiles In African Ancestry Populations With Apol1 Risk Alleles, Xinruo Zhang, Ashley W Scadden, Amarnath Marthi, Victoria L Buchanan, Yishu Qu, Kendra R Ferrier, Brian D Chen, Mariaelisa Graff, Julian Avila, Eric Boerwinkle, Steven Buyske, Clary B Clish, Dan Cruz, Myriam Fornage, Robert E Gerzsten, Christopher R Gignoux, Lashaunta Glover, Lifang Hou, Anne E Justice, Charles Kooperberg, Holly Kramer, Leslie Lange, Ruth J F Loos, Tara Matise, Josyf C Mychaleckyj, Opeyemi A Olabisi, Ulrike Peters, Laura M Raffield, Alex P Reiner, Stephen S Rich, Jerome I Rotter, Kent D Taylor, Bing Yu, Yinan Zheng, Kari E North, Amy K Mottl, Heather M Highland, Maggie A Stanislawski

Faculty, Staff and Student Publications

Key Points:

1. We aimed to elucidate potential methylation, proteomic, and metabolomic mechanisms by which APOL1 variants may be linked to kidney disease.

2. We report distinct methylation profiling between APOL1 risk allele carriers and noncarriers, many near APOL gene family.

3. We report higher APOL1 protein and lower C18:1 cholesteryl ester in two risk allele carriers.

Background: The APOL1 high-risk haplotype has been associated with CKD and the deterioration of kidney function, particularly in populations with West African ancestry. However, the mechanisms by which APOL1 risk variants increase the risk for kidney disease and its progression have not been fully elucidated.

Methods: …

Exploring The Impact Of Reduction In Methamphetamine Use On Sexual Risk Behaviors Among Men Who Have Sex With Men And Women: Findings From The Adapt- 2 Trial, Chukwuemeka N Okafor, Jin H Yoon, Ducel Jean-Berluche, Taryn L Mayes, Steve Shoptaw, Madhukar H Trivedi, Jennifer S Potter, Joy Schmitz

Faculty, Staff and Student Publications

Background: Methamphetamine (MA) use has been linked to engaging in sexual risk behaviors (SRBs) that are associated with HIV/STIs, particularly among men who have sex with men (MSM) and men who have sex with men and women (MSMW; hereafter MSM/W). The objectives of this analysis were to determine whether reduced MA is associated with decreases in SRBs in a sample of MSM/W.

Method: Data came from the ADAPT- 2 trial, a randomized, double-blind, two-stage sequential parallel design trial evaluating extended-release injectable naltrexone (NTX) and oral bupropion (BUP) vs. placebo for MA use disorder. In the first 6 weeks of the …

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 …

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 …