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Real-World Efficacy And Safety Of Amivantamab For Egfr-Mutant Nsclc, Kaiwen Wang, Robyn Du, Nathaniel J Myall, Whitney E Lewis, Natalie Uy, Lingzhi Hong, Ferdinandos Skoulidis, Lauren A Byers, Anne Tsao, Tina Cascone, Jenny Pozadzides, Janet Tu, Marcelo V Negrao, Don L Gibbons, Keunchil Park, Waree Rinsurongkawong, J Jack Lee, David Gandara, Deepti Behl, Catherine A Shu, Jonathan W Riess, Christina Baik, Heather A Wakelee, Ara A Vaporciyan, John V Heymach, Jianjun Zhang, Xiuning Le

Faculty, Staff and Student Publications

Introduction: Amivantamab-vmjw (amivantamab) is a bispecific EGFR/MET antibody approved for patients with advanced NSCLC with EGFR exon 20 insertion mutations, after prior therapy. Nevertheless, the benefits and safety of amivantamab in other EGFR-mutant lung cancer, with or without osimertinib, and with concurrent radiation therapy, are less known.

Methods: We queried the MD Anderson Lung Cancer GEMINI, Fred Hutchinson Cancer Research Center, University of California Davis Comprehensive Cancer Center, and Stanford Cancer Center's database for patients with EGFR-mutant NSCLC treated with amivantamab, not on a clinical trial. The data analyzed included initial response, duration of treatment, and concomitant radiation safety in …

Oxidation Of Hydrogen Sulfide To Polysulfide And Thiosulfate By A Carbon Nanozyme: Therapeutic Implications With An Emphasis On Down Syndrome, Paul J Derry, Anton V Liopo, Karthik Mouli, Emily A Mchugh, Anh T T Vo, Ann Mckelvey, Larry J Suva, Gang Wu, Yan Gao, Kenneth R Olson, James M Tour, Thomas A Kent

Faculty, Staff and Student Publications

Hydrogen sulfide (H2S) is a noxious, potentially poisonous, but necessary gas produced from sulfur metabolism in humans. In Down Syndrome (DS), the production of H2S is elevated and associated with degraded mitochondrial function. Therefore, removing H2S from the body as a stable oxide could be an approach to reducing the deleterious effects of H2S in DS. In this report we describe the catalytic oxidation of hydrogen sulfide (H2S) to polysulfides (HS2+n−) and thiosulfate (S2O32−) by poly(ethylene glycol) hydrophilic carbon clusters (PEG-HCCs) and poly(ethylene glycol) oxidized activated charcoal (PEG-OACs), examples of oxidized carbon nanozymes (OCNs). We show that OCNs oxidize H2S …

Comprehensive Analysis Identifies Variability In Pi3k Pathway Alterations In Triple-Negative Breast Cancer Subtypes, Reva K Basho, Li Zhao, Jason B White, Lei Huo, Roland L Bassett, Elizabeth A Mittendorf, Alastair Thompson, Jennifer K Litton, Naoto Ueno, Banu Arun, Bora Lim, Vicente Valero, Debu Tripathy, Jianhua Zhang, Beatriz E Adrada, Lumarie Santiago, Elizabeth Ravenberg, Sahil Seth, Clinton Yam, Stacy L Moulder, Senthil Damodaran

Faculty, Staff and Student Publications

Purpose: The PI3K pathway is frequently altered in triple-negative breast cancer (TNBC). Limited cell line and human data suggest that TNBC tumors characterized as mesenchymal (M) and luminal androgen receptor (LAR) subtypes have increased incidence of alterations in the PI3K pathway. The impact of PI3K pathway alterations across TNBC subtypes is poorly understood.

Methods: Pretreatment tumor was evaluated from operable TNBC patients enrolled on a clinical trial of neoadjuvant therapy (NAT; A Robust TNBC Evaluation fraMework to Improve Survival [ClinicalTrials.gov identifier: NCT02276443]). Tumors were characterized into seven TNBC subtypes per Pietenpol criteria (basal-like 1, basal-like 2, immunomodulatory, M, mesenchymal …

Watching The Fall Of Roe V Wade: Media Exposure Relates To Us Women's Alcohol Use Intentions, Stacy M Post, Mary C Jobe, Arianne N Malekzadeh, Katarina E Aubuchon, Rebecca K Hoffman, Michelle L Stock, Lisa Bowleg

Faculty, Staff and Student Publications

OBJECTIVE: The Supreme Court of the United States’ decision in Dobbs v. Jackson Women’s Health Organization in June 2022 overturned Roe v. Wade and ended federal protection of abortion rights. Given the drastic policy changes as a result of the ruling and high exposure to media related to abortion, women opposed to the decision may have experienced distress, which could trigger maladaptive coping strategies, such as alcohol use. The present research examined how consuming abortion-related media in the weeks following the Dobbs decision impacted alcohol use intentions among women of reproductive age residing in the 13 “trigger law” states that …

Cholinergic Basal Forebrain Connectivity To The Basolateral Amygdala Modulates Food Intake, Joshua Ortiz-Guzman, Jessica L Swanson, Evelyne K Tantry, Mikhail Kochukov, Kevin Ung, Angela P Addison, Snigdha Srivastava, Benjamin D Belfort, Emily Ji, Sean W Dooling, Sarah A Chen, Qingchun Tong, Benjamin R Arenkiel

Faculty, Staff and Student Publications

Obesity results from excessive caloric input associated with overeating and presents a major public health challenge. The hypothalamus has received significant attention for its role in governing feeding behavior and body weight homeostasis. However, extrahypothalamic brain circuits also regulate appetite and consumption by altering sensory perception, motivation, and reward. We recently discovered a population of basal forebrain cholinergic (BFc) neurons that regulate appetite suppression. Through viral tracing methods in the mouse model, we found that BFc neurons densely innervate the basolateral amygdala (BLA), a limbic structure involved in motivated behaviors. Using channelrhodopsin-assisted circuit mapping, we identified cholinergic responses in BLA …

Lung Cancer In Ever- And Never-Smokers: Findings From Multi-Population Gwas Studies, Yafang Li, Xiangjun Xiao, Jianrong Li, Younghun Han, Chao Cheng, Gail F Fernandes, Shannon E Slewitzke, Susan M Rosenberg, Meng Zhu, Jinyoung Byun, Yohan Bossé, James D Mckay, Demetrios Albanes, Stephen Lam, Adonina Tardon, Chu Chen, Stig E Bojesen, Maria T Landi, Mattias Johansson, Angela Risch, Heike Bickeböller, H-Erich Wichmann, David C Christiani, Gad Rennert, Susanne M Arnold, Gary E Goodman, John K Field, Michael P A Davies, Sanjay Shete, Loïc Le Marchand, Geoffrey Liu, Rayjean J Hung, Angeline S Andrew, Lambertus A Kiemeney, Ryan Sun, Shanbeh Zienolddiny, Kjell Grankvist, Mikael Johansson, Neil E Caporaso, Angela Cox, Yun-Chul Hong, Philip Lazarus, Matthew B Schabath, Melinda C Aldrich, Ann G Schwartz, Ivan Gorlov, Kristen S Purrington, Ping Yang, Yanhong Liu, Joan E Bailey-Wilson, Susan M Pinney, Diptasri Mandal, James C Willey, Colette Gaba, Paul Brennan, Jun Xia, Hongbing Shen, Christopher I Amos

Faculty, Staff and Student Publications

BACKGROUND: Clinical, molecular, and genetic epidemiology studies displayed remarkable differences between ever- and never-smoking lung cancer.

METHODS: We conducted a stratified multi-population (European, East Asian, and African descent) association study on 44,823 ever-smokers and 20,074 never-smokers to identify novel variants that were missed in the non-stratified analysis. Functional analysis including expression quantitative trait loci (eQTL) colocalization and DNA damage assays, and annotation studies were conducted to evaluate the functional roles of the variants. We further evaluated the impact of smoking quantity on lung cancer risk for the variants associated with ever-smoking lung cancer.

RESULTS: Five novel independent loci, GABRA4, intergenic …

Familial Hypercholesterolemia Variant And Cardiovascular Risk In Individuals With Elevated Cholesterol, Yiyi Zhang, Jacqueline S Dron, Brandon K Bellows, Amit V Khera, Junxiu Liu, Pallavi P Balte, Elizabeth C Oelsner, Sami Samir Amr, Matthew S Lebo, Anna Nagy, Gina M Peloso, Pradeep Natarajan, Jerome I Rotter, Cristen Willer, Eric Boerwinkle, Christie M Ballantyne, Pamela L Lutsey, Myriam Fornage, Donald M Lloyd-Jones, Lifang Hou, Bruce M Psaty, Joshua C Bis, James S Floyd, Ramachandran S Vasan, Nancy L Heard-Costa, April P Carson, Michael E Hall, Stephen S Rich, Xiuqing Guo, Dhruv S Kazi, Sarah D De Ferranti, Andrew E Moran

Faculty, Staff and Student Publications

IMPORTANCE: Familial hypercholesterolemia (FH) is a genetic disorder that often results in severely high low-density lipoprotein cholesterol (LDL-C) and high risk of premature coronary heart disease (CHD). However, the impact of FH variants on CHD risk among individuals with moderately elevated LDL-C is not well quantified.

OBJECTIVE: To assess CHD risk associated with FH variants among individuals with moderately (130-189 mg/dL) and severely (≥190 mg/dL) elevated LDL-C and to quantify excess CHD deaths attributable to FH variants in US adults.

DESIGN, SETTING, AND PARTICIPANTS: A total of 21 426 individuals without preexisting CHD from 6 US cohort studies (Atherosclerosis Risk …

Clonal Hematopoiesis Of Indeterminate Potential Is Associated With Acute Kidney Injury, Caitlyn Vlasschaert, Cassianne Robinson-Cohen, Jianchun Chen, Elvis Akwo, Alyssa C Parker, Samuel A Silver, Pavan K Bhatraju, Hannah Poisner, Shirong Cao, Ming Jiang, Yinqiu Wang, Aolei Niu, Edward Siew, Joseph C Van Amburg, Holly J Kramer, Anna Kottgen, Nora Franceschini, Bruce M Psaty, Russell P Tracy, Alvaro Alonso, Dan E Arking, Josef Coresh, Christie M Ballantyne, Eric Boerwinkle, Morgan Grams, Ming-Zhi Zhang, Bryan Kestenbaum, Matthew B Lanktree, Michael J Rauh, Raymond C Harris, Alexander G Bick

Faculty, Staff and Student Publications

Age is a predominant risk factor for acute kidney injury (AKI), yet the biological mechanisms underlying this risk are largely unknown. Clonal hematopoiesis of indeterminate potential (CHIP) confers increased risk for several chronic diseases associated with aging. Here we sought to test whether CHIP increases the risk of AKI. In three population-based epidemiology cohorts, we found that CHIP was associated with a greater risk of incident AKI, which was more pronounced in patients with AKI requiring dialysis and in individuals with somatic mutations in genes other than DNMT3A, including mutations in TET2 and JAK2. Mendelian randomization analyses supported a causal …

Efficient Gene Editing For Heart Disease Via Elip-Based Crispr Delivery System, Xing Yin, Romain Harmancey, Brion Frierson, Jean G Wu, Melanie R Moody, David D Mcpherson, Shao-Ling Huang

Faculty, Staff and Student Publications

Liposomes as carriers for CRISPR/Cas9 complexes represent an attractive approach for cardiovascular gene therapy. A critical barrier to this approach remains the efficient delivery of CRISPR-based genetic materials into cardiomyocytes. Echogenic liposomes (ELIP) containing a fluorescein isothiocyanate-labeled decoy oligodeoxynucleotide against nuclear factor kappa B (ELIP-NF-κB-FITC) were used both in vitro on mouse neonatal ventricular myocytes and in vivo on rat hearts to assess gene delivery efficacy with or without ultrasound. In vitro analysis was then repeated with ELIP containing Cas9-sg-IL1RL1 (interleukin 1 receptor-like 1) RNA to determine the efficiency of gene knockdown. ELIP-NF-κB-FITC without ultrasound showed limited gene delivery in …

The Emerging Importance Of Skull-Brain Interactions In Traumatic Brain Injury, Peixi Zhao, Rui Jin, Bin Zhao, Le Han, Wenjuan Chen, Nina Hao, Yi Cui, Ankit Madan, Joy Awosika, Shane Lloyd, Yili Zhang

Faculty, Staff and Student Publications

Background and Objective

Immune checkpoint inhibitors (ICIs) have been widely applied and studied in the treatment of gastrointestinal (GI) cancers, and have achieved good results. However, in clinical practice, it has been observed that only some patients respond well to ICIs, and some patients may experience various degrees of adverse reactions during the treatment. Timely evaluation of the potential therapeutic effects and adverse reactions of ICIs for patients has important clinical significance. This review aimed to summarize recent progress regarding efficacy-associated biomarkers for ICIs in GI cancer.

Methods

The literature on ICI treatment in GI cancers was searched in the …

Pan-Cancer Proteogenomics Characterization Of Tumor Immunity, Francesca Petralia, Weiping Ma, Tomer M Yaron, Francesca Pia Caruso, Nicole Tignor, Joshua M Wang, Daniel Charytonowicz, Jared L Johnson, Emily M Huntsman, Giacomo B Marino, Anna Calinawan, John Erol Evangelista, Myvizhi Esai Selvan, Shrabanti Chowdhury, Dmitry Rykunov, Azra Krek, Xiaoyu Song, Berk Turhan, Karen E Christianson, David A Lewis, Eden Z Deng, Daniel J B Clarke, Jeffrey R Whiteaker, Jacob J Kennedy, Lei Zhao, Rossana Lazcano Segura, Harsh Batra, Maria Gabriela Raso, Edwin Roger Parra, Rama Soundararajan, Ximing Tang, Yize Li, Xinpei Yi, Shankha Satpathy, Ying Wang, Maciej Wiznerowicz, Tania J González-Robles, Antonio Iavarone, Sara J C Gosline, Boris Reva, Ana I Robles, Alexey I Nesvizhskii, D R Mani, Michael A Gillette, Robert J Klein, Marcin Cieslik, Bing Zhang, Amanda G Paulovich, Robert Sebra, Zeynep H Gümüş, Galen Hostetter, David Fenyö, Gilbert S Omenn, Lewis C Cantley, Avi Ma'ayan, Alexander J Lazar, Michele Ceccarelli, Pei Wang, Clinical Proteomic Tumor Analysis Consortium

Faculty, Staff and Student Publications

Despite the successes of immunotherapy in cancer treatment over recent decades, less than <10%-20% cancer cases have demonstrated durable responses from immune checkpoint blockade. To enhance the efficacy of immunotherapies, combination therapies suppressing multiple immune evasion mechanisms are increasingly contemplated. To better understand immune cell surveillance and diverse immune evasion responses in tumor tissues, we comprehensively characterized the immune landscape of more than 1,000 tumors across ten different cancers using CPTAC pan-cancer proteogenomic data. We identified seven distinct immune subtypes based on integrative learning of cell type compositions and pathway activities. We then thoroughly categorized unique genomic, epigenetic, transcriptomic, and proteomic changes associated with each subtype. Further leveraging the deep phosphoproteomic data, we studied kinase activities in different immune subtypes, which revealed potential subtype-specific therapeutic targets. Insights from this work will facilitate the development of future immunotherapy strategies and enhance precision targeting with existing agents.

Impact Of Electronic Cigarettes On Pediatric, Adolescent And Young Adult Leukemia Patients, Sanila Sarkar, Lea M Stitzlein, Joya Chandra

Faculty, Staff and Student Publications

Electronic cigarettes, which deliver an aerosolized, nicotine-containing product upon inhalation, are a public health issue that continue to gain popularity among adolescents and young adults in the United States. Use of electronic cigarettes is wide, and extends to pediatric patients with multiple comorbidities, including childhood cancer, leaving them vulnerable to further negative health outcomes. Acute leukemias are the most common type of cancer in pediatric populations, and treatment outcomes for these patients are improving; consequently, there is an increased emphasis on the effect of behavioral lifestyle factors on quality of life in survivorship. The rate of electronic cigarette use is …

Comprehensive Characterization Of Ifnγ Signaling In Acute Myeloid Leukemia Reveals Prognostic And Therapeutic Strategies, Bofei Wang, Patrick K Reville, Mhd Yousuf Yassouf, Fatima Z Jelloul, Christopher Ly, Poonam N Desai, Zhe Wang, Pamella Borges, Ivo Veletic, Enes Dasdemir, Jared K Burks, Guilin Tang, Shengnan Guo, Araceli Isabella Garza, Cedric Nasnas, Nicole R Vaughn, Natalia Baran, Qing Deng, Jairo Matthews, Preethi H Gunaratne, Dinler A Antunes, Suhendan Ekmekcioglu, Koji Sasaki, Miriam B Garcia, Branko Cuglievan, Dapeng Hao, Naval Daver, Michael R Green, Marina Konopleva, Andrew Futreal, Sean M Post, Hussein A Abbas

Faculty, Staff and Student Publications

Interferon gamma (IFNγ) is a critical cytokine known for its diverse roles in immune regulation, inflammation, and tumor surveillance. However, while IFNγ levels were elevated in sera of most newly diagnosed acute myeloid leukemia (AML) patients, its complex interplay in AML remains insufficiently understood. We aim to characterize these complex interactions through comprehensive bulk and single-cell approaches in bone marrow of newly diagnosed AML patients. We identify monocytic AML as having a unique microenvironment characterized by IFNγ producing T and NK cells, high IFNγ signaling, and immunosuppressive features. IFNγ signaling score strongly correlates with venetoclax resistance in primary AML patient …

Paired Single-B-Cell Transcriptomics And Receptor Sequencing Reveal Activation States And Clonal Signatures That Characterize B Cells In Acute Myeloid Leukemia, Shengnan Guo, Gopi S Mohan, Bofei Wang, Tianhao Li, Naval Daver, Yuting Zhao, Patrick K Reville, Dapeng Hao, Hussein A Abbas

Faculty, Staff and Student Publications

BACKGROUND: Acute myeloid leukemia (AML) is associated with a dismal prognosis. Immune checkpoint blockade (ICB) to induce antitumor activity in AML patients has yielded mixed results. Despite the pivotal role of B cells in antitumor immunity, a comprehensive assessment of B lymphocytes within AML's immunological microenvironment along with their interaction with ICB remains rather constrained.

METHODS: We performed an extensive analysis that involved paired single-cell RNA and B-cell receptor (BCR) sequencing on 52 bone marrow aspirate samples. These samples included 6 from healthy bone marrow donors (normal), 24 from newly diagnosed AML patients (NewlyDx), and 22 from 8 relapsed or …

Metabolomic Profiles Of Sleep-Disordered Breathing Are Associated With Hypertension And Diabetes Mellitus Development, Ying Zhang, Bing Yu, Qibin Qi, Ali Azarbarzin, Han Chen, Neomi A Shah, Alberto R Ramos, Phyllis C Zee, Jianwen Cai, Martha L Daviglus, Eric Boerwinkle, Robert Kaplan, Peter Y Liu, Susan Redline, Tamar Sofer

Faculty, Staff and Student Publications

Sleep-disordered breathing (SDB) is a prevalent disorder characterized by recurrent episodic upper airway obstruction. Using data from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL), we apply principal component analysis (PCA) to seven SDB-related measures. We estimate the associations of the top two SDB PCs with serum levels of 617 metabolites, in both single-metabolite analysis, and a joint penalized regression analysis. The discovery analysis includes 3299 individuals, with validation in a separate dataset of 1522 individuals. Five metabolite associations with SDB PCs are discovered and replicated. SDB PC1, characterized by frequent respiratory events common in older and male adults, is …

Reply To Ayoub-Charette Et Al Lack Of Biological Plausibility And Major Methodological Issues Cast Doubt On The Association Between Aspartame And Autism Comment On "Fowler Et Al Daily Early-Life Exposures To Diet Soda And Aspartame Are Associated With Autism In Males: A Case-Control Study, Sharon Parten Fowler, David Gimeno Ruiz De Porras, Michael D Swartz, Paula Stigler Granados, Lynne Parsons Heilbrun, Raymond F Palmer

Faculty, Staff and Student Publications

Thank you for the opportunity to respond to the concerns raised by Ayoub-Charette et al [...].

Macromolecular Crowding, Phase Separation, And Homeostasis In The Orchestration Of Bacterial Cellular Functions, Begoña Monterroso, William Margolin, Arnold J Boersma, Germán Rivas, Bert Poolman, Silvia Zorrilla

Faculty, Staff and Student Publications

Macromolecular crowding affects the activity of proteins and functional macromolecular complexes in all cells, including bacteria. Crowding, together with physicochemical parameters such as pH, ionic strength, and the energy status, influences the structure of the cytoplasm and thereby indirectly macromolecular function. Notably, crowding also promotes the formation of biomolecular condensates by phase separation, initially identified in eukaryotic cells but more recently discovered to play key functions in bacteria. Bacterial cells require a variety of mechanisms to maintain physicochemical homeostasis, in particular in environments with fluctuating conditions, and the formation of biomolecular condensates is emerging as one such mechanism. In this …

Potential Value Of A Rapid Syndromic Multiplex Pcr For The Diagnosis Of Native And Prosthetic Joint Infections: A Real-World Evidence Study, Stéphanie Pascual, Brooklyn Noble, Nusreen Ahmad-Saeed, Catherine Aldridge, Simone Ambretti, Sharon Amit, Rachel Annett, Shaan Ashk O'Shea, Anna Maria Barbui, Gavin Barlow, Lucinda Barrett, Mario Berth, Alessandro Bondi, Nicola Boran, Sara E Boyd, Catarina Chaves, Martin Clauss, Peter Davies, Ileana T Dianzo-Delgado, Jaime Esteban, Stefan Fuchs, Lennart Friis-Hansen, Daniel Goldenberger, Andrej Golle, Juha O Groonroos, Ines Hoffmann, Tomer Hoffmann, Harriet Hughes, Marina Ivanova, Peter Jezek, Gwennan Jones, Zeynep Ceren Karahan, Cornelia Lass-Flörl, Frédéric Laurent, Laura Leach, Matilde Lee Horsbøll Pedersen, Caroline Loiez, Maureen Lynch, Robert J Maloney, Martin Marsh, Olivia Milburn, Shanine Mitchell, Luke S P Moore, Lynn Moffat, Marianna Murdjeva, Michael E Murphy, Deepa Nayar, Giacomo Nigrisoli, Fionnuala O'Sullivan, Büşra Öz, Teresa Peach, Christina Petridou, Mojgan Prinz, Mitja Rak, Niamh Reidy, Gian Maria Rossolini, Anne-Laure Roux, Patricia Ruiz-Garbajosa, Kordo Saeed, Llanos Salar-Vidal, Carlos Salas Venero, Mathyruban Selvaratnam, Eric Senneville, Peter Starzengruber, Ben Talbot, Vanessa Taylor, Rihard Trebše, Deborah Wearmouth, Birgit Willinger, Marjan Wouthuyzen-Bakker, Brianne Couturier, Florence Allantaz

Faculty, Staff and Student Publications

Introduction: The BIOFIRE Joint Infection (JI) Panel is a diagnostic tool that uses multiplex-PCR testing to detect microorganisms in synovial fluid specimens from patients suspected of having septic arthritis (SA) on native joints or prosthetic joint infections (PJIs). Methods: A study was conducted across 34 clinical sites in 19 European and Middle Eastern countries from March 2021 to June 2022 to assess the effectiveness of the BIOFIRE JI Panel. Results: A total of 1527 samples were collected from patients suspected of SA or PJI, with an overall agreement of 88.4 % and 85 % respectively between the …

The Brain Structure And Function Abnormalities Of Migraineurs: A Systematic Review And Neuroimaging Meta-Analysis, Wei Ruan, Tao Li, Jaewoong Lee, In Hyuk Bang, Wankun Deng, Xinxin Ma, Seung-Hee Yoo, Boyun Kim, Jiwen Li, Xiaoyi Yuan, Yu A An, Yin-Ying Wang, Yafen Liang, Matthew Deberge, Dongze Zhang, Zhen Zhou, Yanyu Wang, Josh Gorham, Jonathan G Seidman, Christine E Seidman, Sary F Aranki, Ragini Nair, Lei Li, Jagat Narula, Zhongming Zhao, Alemayehu G Abebe, Jochen Daniel Muehlschlegel, Kuang-Lei Tsai, Holger K Eltzschig

Faculty, Staff and Student Publications

Acute myocardial infarction stands as a prominent cause of morbidity and mortality worldwide

Causal Influence Of Linguistic Learning On Perceptual And Conceptual Processing: A Brain-Constrained Deep Neural Network Study Of Proper Names And Category Terms, Phuc T U Nguyen, Malte R Henningsen-Schomers, Friedemann Pulvermüller

Faculty, Staff and Student Publications

Language influences cognitive and conceptual processing, but the mechanisms through which such causal effects are realized in the human brain remain unknown. Here, we use a brain-constrained deep neural network model of category formation and symbol learning and analyze the emergent model's internal mechanisms at the neural circuit level. In one set of simulations, the network was presented with similar patterns of neural activity indexing instances of objects and actions belonging to the same categories. Biologically realistic Hebbian learning led to the formation of instance-specific neurons distributed across multiple areas of the network, and, in addition, to cell assembly circuits …

Energetic Trade-Offs In Migration Decision-Making, Reproductive Effort And Subsequent Parental Care In A Long-Distance Migratory Bird, Alexander R Schindler, Anthony D Fox, Christopher K Wikle, Bart M Ballard, Alyn J Walsh, Seán B A Kelly, Lei Cao, Larry R Griffin, Mitch D Weegman

Faculty, Staff and Student Publications

Migratory species trade-off long-distance movement with survival and reproduction, but the spatio-temporal scales at which these decisions occur are relatively unknown. Technological and statistical advances allow fine-scale study of animal decision-making, improving our understanding of possible causes and therefore conservation management. We quantified effects of reproductive preparation during spring migration on subsequent breeding outcomes, breeding outcomes on autumn migration characteristics and autumn migration characteristics on subsequent parental survival in Greenland white-fronted geese (

Gamma Delta T Cells In Acute Myeloid Leukemia: Biology And Emerging Therapeutic Strategies, Adishwar Rao, Akriti Agrawal, Gautam Borthakur, Venkata Lokesh Battula, Abhishek Maiti

Faculty, Staff and Student Publications

γδ T cells play an important role in disease control in acute myeloid leukemia (AML) and have become an emerging area of therapeutic interest. These cells represent a minor population of T lymphocytes with intrinsic abilities to recognize antigens in a major histocompatibility complex-independent manner and functionally straddle the innate and adaptive immunity interface. AML shows high expression of phosphoantigens and UL-16 binding proteins that activate the Vδ2 and Vδ1 subtypes of γδ T cells, respectively, leading to γδ T cell-mediated cytotoxicity. Insights from murine models and clinical data in humans show improved overall survival, leukemia-free survival, reduced risk of …

Association Of Plasma Ykl-40 With Mri, Csf, And Cognitive Markers Of Brain Health And Dementia, Matthew P Pase, Jayandra J Himali, Raquel Puerta, Alexa S Beiser, Mitzi M Gonzales, Claudia L Satizabal, Qiong Yang, Hugo J Aparicio, Daniel J Kojis, Charles S Decarli, Oscar L Lopez, Will Longstreth, Vilmundur Gudnason, Thomas H Mosley, Joshua C Bis, Alison Fohner, Bruce M Psaty, Mercè Boada, Pablo García-González, Sergi Valero, Marta Marquié, Russell Tracy, Lenore J Launer, Agustín Ruiz, Myriam Fornage, Sudha Seshadri

Faculty, Staff and Student Publications

BACKGROUND AND OBJECTIVES: Higher YKL-40 levels in the CSF are a known biomarker of brain inflammation. We explored the utility of plasma YKL-40 as a biomarker for accelerated brain aging and dementia risk.

METHODS: We performed cross-sectional and prospective analyses of 4 community-based cohorts in the United States or Europe: the Age, Gene/Environment Susceptibility-Reykjavik Study, Atherosclerosis Risk in the Communities study, Coronary Artery Risk Development in Young Adults study, and Framingham Heart Study (FHS). YKL-40 was measured from stored plasma by a single laboratory using Mesoscale Discovery with levels log transformed and standardized within each cohort. Outcomes included MRI total …

Rbpms Regulates Cardiomyocyte Contraction And Cardiac Function Through Rna Alternative Splicing, Peiheng Gan, Zhaoning Wang, Svetlana Bezprozvannaya, John R Mcanally, Wei Tan, Hui Li, Rhonda Bassel-Duby, Ning Liu, Eric N Olson

Faculty, Staff and Student Publications

Aims: RNA binding proteins play essential roles in mediating RNA splicing and are key post-transcriptional regulators in the heart. Our recent study demonstrated that RBPMS (RNA binding protein with multiple splicing) is crucial for cardiac development through modulating mRNA splicing, but little is known about its functions in the adult heart. In this study, we aim to characterize the post-natal cardiac function of Rbpms and its mechanism of action.

Methods and results: We generated a cardiac-specific knockout mouse line and found that cardiac-specific loss of Rbpms caused severe cardiomyocyte contractile defects, leading to dilated cardiomyopathy and early lethality in adult …

Bridging Therapy With Axicabtagene Ciloleucel For Large B-Cell Lymphoma: Results From The Us Lymphoma Car-T Consortium, Michael D Jain, Miriam T Jacobs, Feng Gao, Loretta J Nastoupil, Jay Y Spiegel, Yi Lin, Saurabh Dahiya, Matthew Lunning, Lazaros Lekakis, Patrick Reagan, Olalekan Oluwole, Joseph Mcguirk, Abhinav Deol, Alison R Sehgal, Andre Goy, Brian T Hill, Charalambos Andreadis, Javier Munoz, Julio C Chavez, N Nora Bennani, Aaron P Rapoport, Julie M Vose, David Miklos, Sattva S Neelapu, Frederick L Locke, Armin Ghobadi

Faculty, Staff and Student Publications

During the manufacturing period of autologous chimeric antigen receptor (CAR) T-cell therapy, patients may experience a decline in their condition due to cancer progression. In this study, we investigated the impact of bridging therapy (BT) on the outcome of patients with relapsed/refractory large B-cell lymphoma who received antilymphoma treatment between leukapheresis and axicabtagene ciloleucel (axi-cel) infusion. We conducted our analysis using data from the multicenter US Lymphoma CAR-T Consortium, with a median follow-up of 33 months (range, 4.3-42.1). Out of the 298 patients who underwent leukapheresis, 275 patients received axi-cel. A total 52% of patients (n = 143) who received …

Differential Upregulation Of Th1/Th17-Associated Proteins And Pd-L1 In Granulomatous Mycosis Fungoides, Mario L Marques-Piubelli, Jesus Navarrete, Debora A Ledesma, Courtney W Hudgens, Rossana N Lazcano, Ali Alani, Auris Huen, Madeleine Duvic, Priyadharsini Nagarajan, Phyu P Aung, Ignacio I Wistuba, Jonathan L Curry, Roberto N Miranda, Carlos A Torres-Cabala

Faculty, Staff and Student Publications

Granulomatous Mycosis Fungoides (GMF) is a rare form of mycosis fungoides (MF) characterized by a granulomatous infiltrate associated with the neoplastic lymphoid population and is considered to have a worse prognosis compared with regular MF. The upregulation of the T helper (Th) axis, especially Th17, plays an important role in the pathogenesis of several inflammatory/infectious granulomatous cutaneous diseases, but its role in GMF is still not elucidated to date. In this study, we evaluated the immunohistochemical expression of Th1 (Tbet), Th2 (GATA-3), Th17 (RORγT), T regulatory (Foxp3), and immune checkpoint (IC) (PD-1 and PD-L1) markers in a cohort of patients …

Clinical Benefit From Docetaxel +/- Ramucirumab Is Not Associated With Mutation Status In Metastatic Non-Small-Cell Lung Cancer Patients Who Progressed On Platinum Doublets And Immunotherapy, Kang Qin, Kaiwen Wang, Shenduo Li, Lingzhi Hong, Priyadharshini Padmakumar, Rinsurongkawong Waree, Shawna M Hubert, Xiuning Le, Natalie Vokes, Kunal Rai, Ara Vaporciyan, Don L Gibbons, John V Heymach, J Jack Lee, Scott E Woodman, Caroline Chung, David A Jaffray, Mehmet Altan, Yanyan Lou, Jianjun Zhang

Faculty, Staff and Student Publications

Docetaxel +/- ramucirumab remains the standard-of-care therapy for patients with metastatic non-small-cell lung cancer (NSCLC) after progression on platinum doublets and immune checkpoint inhibitors (ICIs). The aim of our study was to investigate whether the cancer gene mutation status was associated with clinical benefits from docetaxel +/- ramucirumab. We also investigated whether platinum/taxane-based regimens offered a better clinical benefit in this patient population. A total of 454 patients were analyzed (docetaxel +/- ramucirumab n=381; platinum/taxane-based regimens n=73). Progression-free survival (PFS) and overall survival (OS) were compared among different subpopulations with different cancer gene mutations and between patients who received docetaxel …

The Future Of Targeted Therapy For Leiomyosarcoma, Ryan A Denu, Amanda M Dann, Emily Z Keung, Michael S Nakazawa, Elise F Nassif Haddad

Faculty, Staff and Student Publications

Leiomyosarcoma (LMS) is an aggressive subtype of soft tissue sarcoma that arises from smooth muscle cells, most commonly in the uterus and retroperitoneum. LMS is a heterogeneous disease with diverse clinical and molecular characteristics that have yet to be fully understood. Molecular profiling has uncovered possible targets amenable to treatment, though this has yet to translate into approved targeted therapies in LMS. This review will explore historic and recent findings from molecular profiling, highlight promising avenues of current investigation, and suggest possible future strategies to move toward the goal of molecularly matched treatment of LMS. We focus on targeting the …

Endoscopic Hyperspectral Imaging System To Discriminate Tissue Characteristics In Tissue Phantom And Orthotopic Mouse Pancreatic Tumor Model, Na Eun Mun, Thi Kim Chi Tran, Dong Hui Park, Jin Hee Im, Jae Il Park, Thanh Dat Le, Young Jin Moon, Seong-Young Kwon, Su Woong Yoo

Faculty, Staff and Student Publications

In this study, we developed an endoscopic hyperspectral imaging (eHSI) system and evaluated its performance in analyzing tissues within tissue phantoms and orthotopic mouse pancreatic tumor models. Our custom-built eHSI system incorporated a liquid crystal tunable filter. To assess its tissue discrimination capabilities, we acquired images of tissue phantoms, distinguishing between fat and muscle regions. The system underwent supervised training using labeled samples, and this classification model was then applied to other tissue phantom images for evaluation. In the tissue phantom experiment, the eHSI effectively differentiated muscle from fat and background tissues. The precision scores regarding fat tissue classification were …

A Model-Agnostic Computational Method For Discovering Gene–Phenotype Relationships And Inferring Gene Networks Via In Silico Gene Perturbation, Rastko Stojšin, Xiangning Chen, Zhongming Zhao

Faculty, Staff and Student Publications

Background Deep learning architectures have advanced genotype‒phenotype mappings with precision but often obscure the roles of specific genes and their interactions. Our research introduces a model-agnostic computational methodology, capitalizing on the analytical strengths of deep learning models to serve as biological proxies, enabling interpretation of key gene interactions and their impact on phenotypic outcomes. The objective of this research is to refine the understanding of genetic networks in complex traits by leveraging the nuanced decision-making of advanced models.

Results Testing was conducted across several computational models representing varying levels of complexity trained on gene expression datasets for the prediction of …