Medical Specialties Commons^™

Genetic Or Pharmacological Ghsr Blockade Has Sexually Dimorphic Effects In Rodents On A High-Fat Diet, András H Lékó, Adriana Gregory-Flores, Renata C N Marchette, Juan L Gomez, Janaina C M Vendruscolo, Vez Repunte-Canonigo, Vicky Choung, Sara L Deschaine, Kimberly E Whiting, Shelley N Jackson, Maria Paula Cornejo, Mario Perello, Zhi-Bing You, Michael Eckhaus, Karuna Rasineni, Kim D Janda, Barry Zorman, Pavel Sumazin, George F Koob, Michael Michaelides, Pietro P Sanna, Leandro F Vendruscolo, Lorenzo Leggio

Faculty, Staff and Students Publications

The stomach-derived hormone ghrelin regulates essential physiological functions. The ghrelin receptor (GHSR) has ligand-independent actions; therefore, GHSR gene deletion may be a reasonable approach to investigate the role of this system in feeding behaviors and diet-induced obesity (DIO). Here, we investigate the effects of a long-term (12-month) high-fat (HFD) versus regular diet on obesity-related measures in global GHSR-KO and wild-type (WT) Wistar male and female rats. Our main findings are that the GHSR gene deletion protects against DIO and decreases food intake during HFD in male but not in female rats. GHSR gene deletion increases thermogenesis and brain glucose uptake …

Ver-Net: A Hybrid Transfer Learning Model For Lung Cancer Detection Using Ct Scan Images, Anindita Saha, Shahid Mohammad Ganie, Pijush Kanti Dutta Pramanik, Rakesh Kumar Yadav, Saurav Mallik, Zhongming Zhao

Faculty, Staff and Student Publications

BACKGROUND: Lung cancer is the second most common cancer worldwide, with over two million new cases per year. Early identification would allow healthcare practitioners to handle it more effectively. The advancement of computer-aided detection systems significantly impacted clinical analysis and decision-making on human disease. Towards this, machine learning and deep learning techniques are successfully being applied. Due to several advantages, transfer learning has become popular for disease detection based on image data.

METHODS: In this work, we build a novel transfer learning model (VER-Net) by stacking three different transfer learning models to detect lung cancer using lung CT scan images. …

Validation Of Human Telomere Length Multi-Ancestry Meta-Analysis Association Signals Identifies Pop5 And Kbtbd6 As Human Telomere Length Regulation Genes, Rebecca Keener, Surya B Chhetri, Carla J Connelly, Margaret A Taub, Matthew P Conomos, Joshua Weinstock, Bohan Ni, Benjamin Strober, Stella Aslibekyan, Paul L Auer, Lucas Barwick, Lewis C Becker, John Blangero, Eugene R Bleecker, Jennifer A Brody, Brian E Cade, Juan C Celedon, Yi-Cheng Chang, L Adrienne Cupples, Brian Custer, Barry I Freedman, Mark T Gladwin, Susan R Heckbert, Lifang Hou, Marguerite R Irvin, Carmen R Isasi, Jill M Johnsen, Eimear E Kenny, Charles Kooperberg, Ryan L Minster, Take Naseri, Satupa'itea Viali, Sergei Nekhai, Nathan Pankratz, Patricia A Peyser, Kent D Taylor, Marilyn J Telen, Baojun Wu, Lisa R Yanek, Ivana V Yang, Christine Albert, Donna K Arnett, Allison E Ashley-Koch, Kathleen C Barnes, Joshua C Bis, Thomas W Blackwell, Eric Boerwinkle, Esteban G Burchard, April P Carson, Zhanghua Chen, Yii-Der Ida Chen, Dawood Darbar, Mariza De Andrade, Patrick T Ellinor, Myriam Fornage, Bruce D Gelb, Frank D Gilliland, Jiang He, Talat Islam, Stefan Kaab, Sharon L R Kardia, Shannon Kelly, Barbara A Konkle, Rajesh Kumar, Ruth J F Loos, Fernando D Martinez, Stephen T Mcgarvey, Deborah A Meyers, Braxton D Mitchell, Courtney G Montgomery, Kari E North, Nicholette D Palmer, Juan M Peralta, Benjamin A Raby, Susan Redline, Stephen S Rich, Dan Roden, Jerome I Rotter, Ingo Ruczinski, David Schwartz, Frank Sciurba, M Benjamin Shoemaker, Edwin K Silverman, Moritz F Sinner, Nicholas L Smith, Albert V Smith, Hemant K Tiwari, Ramachandran S Vasan, Scott T Weiss, L Keoki Williams, Yingze Zhang, Elad Ziv, Laura M Raffield, Alexander P Reiner, Nhlbi Trans-Omics For Precision Medicine (Topmed) Consortium, Topmed Hematology And Hemostasis Working Group, Topmed Structural Variation Working Group, Marios Arvanitis, Carol W Greider, Rasika A Mathias, Alexis Battle

Faculty, Staff and Student Publications

Genome-wide association studies (GWAS) have become well-powered to detect loci associated with telomere length. However, no prior work has validated genes nominated by GWAS to examine their role in telomere length regulation. We conducted a multi-ancestry meta-analysis of 211,369 individuals and identified five novel association signals. Enrichment analyses of chromatin state and cell-type heritability suggested that blood/immune cells are the most relevant cell type to examine telomere length association signals. We validated specific GWAS associations by overexpressing KBTBD6 or POP5 and demonstrated that both lengthened telomeres. CRISPR/Cas9 deletion of the predicted causal regions in K562 blood cells reduced expression of …

Brain Cell-Type Shifts In Alzheimer’S Disease, Autism, And Schizophrenia Interrogated Using Methylomics And Genetics, Chloe X Yap, Daniel D Vo, Matthew G Heffel, Arjun Bhattacharya, Cindy Wen, Yuanhao Yang, Kathryn E Kemper, Jian Zeng, Zhili Zheng, Zhihong Zhu, Eilis Hannon, Dorothea Seiler Vellame, Alice Franklin, Christa Caggiano, Brie Wamsley, Daniel H Geschwind, Noah Zaitlen, Alexander Gusev, Bogdan Pasaniuc, Jonathan Mill, Chongyuan Luo, Michael J Gandal

Faculty, Staff and Student Publications

Few neuropsychiatric disorders have replicable biomarkers, prompting high-resolution and large-scale molecular studies. However, we still lack consensus on a more foundational question: whether quantitative shifts in cell types-the functional unit of life-contribute to neuropsychiatric disorders. Leveraging advances in human brain single-cell methylomics, we deconvolve seven major cell types using bulk DNA methylation profiling across 1270 postmortem brains, including from individuals diagnosed with Alzheimer's disease, schizophrenia, and autism. We observe and replicate cell-type compositional shifts for Alzheimer's disease (endothelial cell loss), autism (increased microglia), and schizophrenia (decreased oligodendrocytes), and find age- and sex-related changes. Multiple layers of evidence indicate that endothelial …

Evaluating Performance And Applications Of Sample-Wise Cell Deconvolution Methods On Human Brain Transcriptomic Data, Rujia Dai, Tianyao Chu, Ming Zhang, Xuan Wang, Alexandre Jourdon, Feinan Wu, Jessica Mariani, Flora M Vaccarino, Donghoon Lee, John F Fullard, Gabriel E Hoffman, Panos Roussos, Yue Wang, Xusheng Wang, Dalila Pinto, Sidney H Wang, Chunling Zhang, Psychencode Consortium, Chao Chen, Chunyu Liu

Faculty, Staff and Student Publications

Sample-wise deconvolution methods estimate cell-type proportions and gene expressions in bulk tissue samples, yet their performance and biological applications remain unexplored, particularly in human brain transcriptomic data. Here, nine deconvolution methods were evaluated with sample-matched data from bulk tissue RNA sequencing (RNA-seq), single-cell/nuclei (sc/sn) RNA-seq, and immunohistochemistry. A total of 1,130,767 nuclei per cells from 149 adult postmortem brains and 72 organoid samples were used. The results showed the best performance of dtangle for estimating cell proportions and bMIND for estimating sample-wise cell-type gene expressions. For eight brain cell types, 25,273 cell-type eQTLs were identified with deconvoluted expressions (decon-eQTLs). The …

Profiling Complex Repeat Expansions In Rfc1 In Parkinson’S Disease, Pilar Alvarez Jerez, Kensuke Daida, Abigail Miano-Burkhardt, Hirotaka Iwaki, Laksh Malik, Guillaume Cogan, Mary B Makarious, Roisin Sullivan, Jana Vandrovcova, Jinhui Ding, J Raphael Gibbs, Androo Markham, Mike A Nalls, Rupesh K Kesharwani, Fritz J Sedlazeck, Bradford Casey, John Hardy, Henry Houlden, Cornelis Blauwendraat, Andrew B Singleton, Kimberley J Billingsley

Faculty, Staff and Students Publications

A biallelic (AAGGG) expansion in the poly(A) tail of an AluSx3 transposable element within the gene RFC1 is a frequent cause of cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS), and more recently, has been reported as a rare cause of Parkinson's disease (PD) in the Finnish population. Here, we investigate the prevalence of RFC1 (AAGGG) expansions in PD patients of non-Finnish European ancestry in 1609 individuals from the Parkinson's Progression Markers Initiative study. We identified four PD patients carrying the biallelic RFC1 (AAGGG) expansion and did not identify any carriers in controls.

Dynamic Cbct Imaging Using Prior Model-Free Spatiotemporal Implicit Neural Representation (Pmf-Stinr), Hua-Chieh Shao, Tielige Mengke, Tinsu Pan, You Zhang

Faculty, Staff and Student Publications

Objective. Dynamic cone-beam computed tomography (CBCT) can capture high-spatial-resolution, time-varying images for motion monitoring, patient setup, and adaptive planning of radiotherapy. However, dynamic CBCT reconstruction is an extremely ill-posed spatiotemporal inverse problem, as each CBCT volume in the dynamic sequence is only captured by one or a few x-ray projections, due to the slow gantry rotation speed and the fast anatomical motion (e.g. breathing).Approach. We developed a machine learning-based technique, prior-model-free spatiotemporal implicit neural representation (PMF-STINR), to reconstruct dynamic CBCTs from sequentially acquired x-ray projections. PMF-STINR employs a joint image reconstruction and registration approach to address the …

Prediction Of Disease-Free Survival For Precision Medicine Using Cooperative Learning On Multi-Omic Data, Georg Hahn, Dmitry Prokopenko, Julian Hecker, Sharon M Lutz, Kristina Mullin, Leinal Sejour, Winston Hide, Ioannis Vlachos, Stacia Desantis, Rudolph E Tanzi, Christoph Lange

Faculty, Staff and Student Publications

In precision medicine, both predicting the disease susceptibility of an individual and forecasting its disease-free survival are areas of key research. Besides the classical epidemiological predictor variables, data from multiple (omic) platforms are increasingly available. To integrate this wealth of information, we propose new methodology to combine both cooperative learning, a recent approach to leverage the predictive power of several datasets, and polygenic hazard score models. Polygenic hazard score models provide a practitioner with a more differentiated view of the predicted disease-free survival than the one given by merely a point estimate, for instance computed with a polygenic risk score. …

Gte: A Graph Learning Framework For Prediction Of T-Cell Receptors And Epitopes Binding Specificity, Feng Jiang, Yuzhi Guo, Hehuan Ma, Saiyang Na, Wenliang Zhong, Yi Han, Tao Wang, Junzhou Huang

Faculty, Staff and Student Publications

The interaction between T-cell receptors (TCRs) and peptides (epitopes) presented by major histocompatibility complex molecules (MHC) is fundamental to the immune response. Accurate prediction of TCR–epitope interactions is crucial for advancing the understanding of various diseases and their prevention and treatment. Existing methods primarily rely on sequence-based approaches, overlooking the inherent topology structure of TCR–epitope interaction networks. In this study, we present , a novel heterogeneous Graph neural network model based on inductive learning to capture the topological structure between TCRs and Epitopes. Furthermore, we address the challenge of constructing negative samples within the graph by proposing a dynamic edge …

Androgen Deprivation Induces Neuroendocrine Phenotypes In Prostate Cancer Cells Through Creb1/Ezh2-Mediated Downregulation Of Rest, Dayong Zheng, Yan Zhang, Sukjin Yang, Ning Su, Michael Bakhoum, Guoliang Zhang, Samira Naderinezhad, Zhengmei Mao, Zheng Wang, Ting Zhou, Wenliang Li

Faculty, Staff and Student Publications

Although effective initially, prolonged androgen deprivation therapy (ADT) promotes neuroendocrine differentiation (NED) and prostate cancer (PCa) progression. It is incompletely understood how ADT transcriptionally induces NE genes in PCa cells. CREB1 and REST are known to positively and negatively regulate neuronal gene expression in the brain, respectively. No direct link between these two master neuronal regulators has been elucidated in the NED of PCa. We show that REST mRNA is downregulated in NEPC cell and mouse models, as well as in patient samples. Phenotypically, REST overexpression increases ADT sensitivity, represses NE genes, inhibits colony formation in culture, and xenograft tumor …

Photochemical And Biological Dual-Effects Enhance The Inhibition Of Photosensitizers For Tumour Growth, Huiyu Niu, Yang Liu, Yafu Wang, Yonggang Yang, Ge Wang, Tony D James, Jonathan L Sessler, Hua Zhang

Faculty, Staff and Student Publications

Photosensitizers typically rely on a singular photochemical reaction to generate reactive oxygen species, which can then inhibit or eradicate lesions. However, photosensitizers often exhibit limited therapeutic efficiency due to their reliance on a single photochemical effect. Herein, we propose a new strategy that integrates the photochemical effect (type-I photochemical effect) with a biological effect (proton sponge effect). To test our strategy, we designed a series of photosensitizers (ZZ-sers) based on the naphthalimide molecule. ZZ-sers incorporate both a p-toluenesulfonyl moiety and weakly basic groups to activate the proton sponge effect while simultaneously strengthening the type-I photochemical effect, resulting in enhanced …

Age-Specific Induction Of Mutant P53 Drives Clonal Hematopoiesis And Acute Myeloid Leukemia In Adult Mice, Rasoul Pourebrahim, Rafael Heinz Montoya, Hiroki Akiyama, Lauren Ostermann, Shayuan Khazaei, Muharrem Muftuoglu, Natalia Baran, Ran Zhao, Tom Lesluyes, Bin Liu, Joseph D Khoury, Mihai Gagea, Peter Van Loo, Michael Andreeff

Faculty, Staff and Student Publications

The investigation of the mechanisms behind p53 mutations in acute myeloid leukemia (AML) has been limited by the lack of suitable mouse models, which historically have resulted in lymphoma rather than leukemia. This study introduces two new AML mouse models. One model induces mutant p53 and Mdm2 haploinsufficiency in early development, showing the role of Mdm2 in myeloid-biased hematopoiesis and AML predisposition, independent of p53. The second model mimics clonal hematopoiesis by inducing mutant p53 in adult hematopoietic stem cells, demonstrating that the timing of p53 mutation determines AML vs. lymphoma development. In this context, age-related changes in hematopoietic stem …

Selective Refueling Of Car T Cells Using Ada1 And Cd26 Boosts Antitumor Immunity, Yue Hu, Abhijit Sarkar, Kevin Song, Sara Michael, Magnus Hook, Ruoning Wang, Andras Heczey, Xiaotong Song

Faculty, Staff and Student Publications

Chimeric antigen receptor (CAR) T cell therapy is hindered in solid tumor treatment due to the immunosuppressive tumor microenvironment and suboptimal T cell persistence. Current strategies do not address nutrient competition in the microenvironment. Hence, we present a metabolic refueling approach using inosine as an alternative fuel. CAR T cells were engineered to express membrane-bound CD26 and cytoplasmic adenosine deaminase 1 (ADA1), converting adenosine to inosine. Autocrine secretion of ADA1 upon CD3/CD26 stimulation activates CAR T cells, improving migration and resistance to transforming growth factor β1 suppression. Fusion of ADA1 with anti-CD3 scFv further boosts inosine production and minimizes tumor …

Lacl3-Based Sodium Halide Solid Electrolytes With High Ionic Conductivity For All-Solid-State Batteries, Chengyu Fu, Yifan Li, Wenjie Xu, Xuyong Feng, Weijian Gu, Jue Liu, Wenwen Deng, Wei Wang, A M Milinda Abeykoon, Laisuo Su, Lingyun Zhu, Xiaojun Wu, Hongfa Xiang

Faculty, Staff and Student Publications

To enable high performance of all solid-state batteries, a catholyte should demonstrate high ionic conductivity, good compressibility and oxidative stability. Here, a LaCl3-based Na+ superionic conductor (Na1−xZrxLa1−xCl4) with high ionic conductivity of 2.9 × 10−4 S cm−1 (30 °C), good compressibility and high oxidative potential (3.80 V vs. Na2Sn) is prepared via solid state reaction combining mechanochemical method. X-ray diffraction reveals a hexagonal structure (P63/m) of Na1−xZrxLa1−xCl4, with Na+ ions forming a one-dimensional diffusion channel along the c-axis. First-principle calculations combining with …

Targeting The Substrate For Atrial Fibrillation: Jacc Review Topic Of The Week, Mark D Mccauley, Gianluca Iacobellis, Na Li, Stanley Nattel, Jeffrey J Goldberger

Faculty, Staff and Students Publications

The identification of the pulmonary veins as a trigger source for atrial fibrillation (AF) has established pulmonary vein isolation (PVI) as a key target for AF ablation. However, PVI alone does not prevent recurrent AF in many patients, and numerous additional ablation strategies have failed to improve on PVI outcomes. This therapeutic limitation may be due, in part, to a failure to identify and intervene specifically on the pro-fibrillatory substrate within the atria and pulmonary veins. In this review paper, we highlight several emerging approaches with clinical potential that target atrial cardiomyopathy-the underlying anatomic, electrical, and/or autonomic disease affecting the …

Generalizing Parkinson’S Disease Detection Using Keystroke Dynamics: A Self-Supervised Approach, Shikha Tripathi, Alejandro Acien, Ashley A Holmes, Teresa Arroyo-Gallego, Luca Giancardo

Faculty, Staff and Student Publications

Objective: Passive monitoring of touchscreen interactions generates keystroke dynamic signals that can be used to detect and track neurological conditions such as Parkinson's disease (PD) and psychomotor impairment with minimal burden on the user. However, this typically requires datasets with clinically confirmed labels collected in standardized environments, which is challenging, especially for a large subject pool. This study validates the efficacy of a self-supervised learning method in reducing the reliance on labels and evaluates its generalizability.

Materials and methods: We propose a new type of self-supervised loss combining Barlow Twins loss, which attempts to create similar feature representations with reduced …

Il-2-Free Tumor-Infiltrating Lymphocyte Therapy With Pd-1 Blockade Demonstrates Potent Efficacy In Advanced Gynecologic Cancer, Jing Guo, Chunyan Wang, Ning Luo, Yuliang Wu, Wei Huang, Jihui Zhu, Weihui Shi, Jinye Ding, Yao Ge, Chunhong Liu, Zhen Lu, Robert C Bast, Guihai Ai, Weihong Yang, Rui Wang, Caixia Li, Rong Chen, Shupeng Liu, Huajun Jin, Binghui Zhao, Zhongping Cheng

Faculty, Staff and Student Publications

BACKGROUND: Tumor-infiltrating lymphocyte (TIL) therapy has been restricted by intensive lymphodepletion and high-dose intravenous interleukin-2 (IL-2) administration. To address these limitations, we conducted preclinical and clinical studies to evaluate the safety, antitumor activity, and pharmacokinetics of an innovative modified regimen in patients with advanced gynecologic cancer.

METHODS: Patient-derived xenografts (PDX) were established from a local recurrent cervical cancer patient. TILs were expanded ex vivo from minced tumors without feeder cells in the modified TIL therapy regimen. Patients underwent low-dose cyclophosphamide lymphodepletion followed by TIL infusion without intravenous IL-2. The primary endpoint was safety; the secondary endpoints included objective response rate, …

Developing A Membrane-Proximal Cd33-Targeting Car T Cell, Ruby Freeman, Sanam Shahid, Abdul G Khan, Serena C Mathew, Sydney Souness, Erin R Burns, Jasmine S Um, Kento Tanaka, Winson Cai, Sarah Yoo, Andrew Dunbar, Young Park, Devin Mcavoy, Kinga K Hosszu, Ross L Levine, Jaap Jan Boelens, Ivo C Lorenz, Renier J Brentjens, Anthony F Daniyan

Faculty, Staff and Student Publications

BACKGROUND: CD33 is a tractable target in acute myeloid leukemia (AML) for chimeric antigen receptor (CAR) T cell therapy, but clinical success is lacking.

METHODS: We developed 3P14HLh28Z, a novel CD33-directed CD28/CD3Z-based CAR T cell derived from a high-affinity binder obtained through membrane-proximal fragment immunization in humanized mice.

RESULTS: We found that immunization exclusively with the membrane-proximal domain of CD33 is necessary for identification of membrane-proximal binders in humanized mice. Compared with clinically validated lintuzumab-based CAR T cells targeting distal CD33 epitopes, 3P14HLh28Z showed enhanced in vitro functionality as well as superior tumor control and increased overall survival in both …

A Novel Positive-Contrast Magnetic Resonance Imaging Line Marker For High-Dose-Rate (Hdr) Mri-Assisted Radiosurgery (Mars), Li Wang, Yao Ding, Teresa L Bruno, R Jason Stafford, Eric Lin, Tharakeswara K Bathala, Jeremiah W Sanders, Matthew S Ning, Jingfei Ma, Ann H Klopp, Aradhana Venkatesan, Jihong Wang, Karen S Martirosyan, Steven J Frank

Faculty, Staff and Student Publications

Magnetic resonance imaging (MRI) can facilitate accurate organ delineation and optimal dose distributions in high-dose-rate (HDR) MRI-Assisted Radiosurgery (MARS). Its use for this purpose has been limited by the lack of positive-contrast MRI markers that can clearly delineate the lumen of the HDR applicator and precisely show the path of the HDR source on T1- and T2-weighted MRI sequences. We investigated a novel MRI positive-contrast HDR brachytherapy or interventional radiotherapy line marker, C4:S, consisting of C4 (visible on T1-weighted images) complexed with saline. Longitudinal relaxation time (T1) and transverse relaxation time (T2) for C4:S were measured on a 1.5 T …

Multiple Myeloma Patients With A Long Remission After Autologous Hematopoietic Stem Cell Transplantation, Oren Pasvolsky, Zhongya Wang, Denái R Milton, Mark R Tanner, Qaiser Bashir, Samer Srour, Neeraj Saini, Paul Lin, Jeremy Ramdial, Yago Nieto, Guilin Tang, Partow Kebriaei, Yosra Aljawai, Hina N Khan, Hans C Lee, Christine Ye, Krina K Patel, Sheeba K Thomas, Robert Z Orlowski, Elizabeth J Shpall, Richard E Champlin, Muzaffar H Qazilbash

Faculty, Staff and Student Publications

Autologous stem cell transplantation (autoHCT) is considered standard of care for newly diagnosed multiple myeloma (MM). Although most patients eventually progress after autoHCT, a small proportion achieve a durable response. In this retrospective study we included 1576 patients, 244 (15%) of whom were long-term responders (LTR), defined as having a progression-free survival (PFS) of ≥8 years after transplant. Patients in the LTR group were younger than the non-LTR group (median age 58.4 vs. 59.5 years; p = 0.012), less likely to have high-risk cytogenetics (4% vs. 14%; p < 0.001), more often had

Changes In Walking Function And Neural Control Following Pelvic Cancer Surgery With Reconstruction, Geng Li, Di Ao, Marleny M Vega, Payam Zandiyeh, Shuo-Hsiu Chang, Alexander N Penny, Valerae O Lewis, Benjamin J Fregly

Faculty, Staff and Student Publications

Introduction: Surgical planning and custom prosthesis design for pelvic cancer patients are challenging due to the unique clinical characteristics of each patient and the significant amount of pelvic bone and hip musculature often removed. Limb-sparing internal hemipelvectomy surgery with custom prosthesis reconstruction has become a viable option for this patient population. However, little is known about how post-surgery walking function and neural control change from pre-surgery conditions.

Methods: This case study combined comprehensive walking data (video motion capture, ground reaction, and electromyography) with personalized neuromusculoskeletal computer models to provide a thorough assessment of pre- to post-surgery changes in walking function …

Tumor Niche Network-Defined Subtypes Predict Immunotherapy Response Of Esophageal Squamous Cell Cancer, Kyung-Pil Ko, Shengzhe Zhang, Yuanjian Huang, Bongjun Kim, Gengyi Zou, Sohee Jun, Jie Zhang, Yahui Zhao, Cecilia Martin, Karen J Dunbar, Gizem Efe, Anil K Rustgi, Hiroshi Nakagawa, Haiyang Zhang, Zhihua Liu, Jae-Il Park

Faculty, Staff and Student Publications

Despite the promising outcomes of immune checkpoint inhibitors (ICIs), resistance to ICI presents a new challenge. Therefore, selecting patients for specific ICI applications is crucial for maximizing therapeutic efficacy. Herein, we curated 69 human esophageal squamous cell cancer (ESCC) patients' tumor microenvironment (TME) single-cell transcriptomic datasets to subtype ESCC. Integrative analyses of the cellular network and transcriptional signatures of T cells and myeloid cells define distinct ESCC subtypes characterized by T cell exhaustion, and interleukin (IL) and interferon (IFN) signaling. Furthermore, this approach classifies ESCC patients into ICI responders and non-responders, as validated by whole tumor transcriptomes and liquid biopsy-based …

Phase 1b Study Of Batiraxcept In Combination With Durvalumab In Patients With Platinum-Resistant Ovarian Cancer, Anne Knisely, Emily M Hinchcliff, Elisabeth Gardiner, Reshma Rangwala, Kathryn Lito, Bryan Fellman, Ying Yuan, Anil K Sood, Shannon N Westin, Karen H Lu, Amir A Jazaeri

Faculty, Staff and Student Publications

Combining an immune checkpoint inhibitor with batiraxcept (AVB-S6-500), an AXL inhibitor that acts via selective binding to growth arrest-specific protein 6 (GAS6), may improve anti-tumor immunity in platinum-resistant ovarian cancer (PROC). This phase 1b trial of durvalumab in combination with escalating doses of batiraxcept enrolled patients with recurrent PROC (NCT04019288). The primary objective was to determine the toxicity profile of the combination. Eleven patients were enrolled on the trial. No dose-limiting toxicities were observed, and no objective responses were noted. Median progression free survival (PFS) was 1.81 months (95% confidence interval (CI) 1.71–2.40), and median overall survival (OS) was 4.53 …

Dynamic Visual Acuity, Vestibulo-Ocular Reflex, And Visual Field In National Football League (Nfl) Officiating: Physiology And Visualization Engineering For 3d Virtual On-Field Training, Joshua Ong, Nicole V Carrabba, Ethan Waisberg, Nasif Zaman, Hamza Memon, Nicholas Panzo, Virginia A Lee, Prithul Sarker, Ashtyn Z Vogt, Noor Laylani, Alireza Tavakkoli, Andrew G Lee

Faculty, Staff and Student Publications

The ability to make on-field, split-second decisions is critical for National Football League (NFL) game officials. Multiple principles in visual function are critical for accuracy and precision of these play calls, including foveation time and unobstructed line of sight, static visual acuity, dynamic visual acuity, vestibulo-ocular reflex, and sufficient visual field. Prior research has shown that a standardized curriculum in these neuro-ophthalmic principles have demonstrated validity and self-rated improvements in understanding, confidence, and likelihood of future utilization by NFL game officials to maximize visual performance during officiating. Virtual reality technology may also be able to help optimize understandings of specific …

The Long-Term Effects Of Blood Urea Nitrogen Levels On Cardiovascular Disease And All-Cause Mortality In Diabetes: A Prospective Cohort Study, Hongfang Liu, Xiaoqin Xin, Jinghui Gan, Jungao Huang

Faculty, Staff and Student Publications

BACKGROUND: The long-term effects of blood urea nitrogen(BUN) in patients with diabetes remain unknown. Current studies reporting the target BUN level in patients with diabetes are also limited. Hence, this prospective study aimed to explore the relationship of BUN with all-cause and cardiovascular mortalities in patients with diabetes.

METHODS: In total, 10,507 participants with diabetes from the National Health and Nutrition Examination Survey (1999-2018) were enrolled. The causes and numbers of deaths were determined based on the National Death Index mortality data from the date of NHANES interview until follow-up (December 31, 2019). Multivariate Cox proportional hazard regression models were …

Ael Transformed From Post-Et Myelofibrosis With A Sinusoidal Pattern, Jak2 Mutation, And Biallelic Tp53 Inactivation, Qing Wei, M James You

Faculty, Staff and Student Publications

No abstract provided.

Unraveling Etc Complex I Function In Ferroptosis Reveals A Potential Ferroptosis-Inducing Therapeutic Strategy For Lkb1-Deficient Cancers, Chao Mao, Guang Lei, Amber Horbath, Min Wang, Zhengze Lu, Yuelong Yan, Xiaoguang Liu, Lavanya Kondiparthi, Xiong Chen, Jun Cheng, Qidong Li, Zhihao Xu, Li Zhuang, Bingliang Fang, Joseph R Marszalek, Masha V Poyurovsky, Kellen Olszewski, Boyi Gan

Faculty, Staff and Student Publications

The role of the mitochondrial electron transport chain (ETC) in regulating ferroptosis is not fully elucidated. Here, we reveal that pharmacological inhibition of the ETC complex I reduces ubiquinol levels while decreasing ATP levels and activating AMP-activated protein kinase (AMPK), the two effects known for their roles in promoting and suppressing ferroptosis, respectively. Consequently, the impact of complex I inhibitors on ferroptosis induced by glutathione peroxidase 4 (GPX4) inhibition is limited. The pharmacological inhibition of complex I in LKB1-AMPK-inactivated cells, or genetic ablation of complex I (which does not trigger apparent AMPK activation), abrogates the AMPK-mediated ferroptosis-suppressive effect and sensitizes …

Enhancer Switching In Cell Lineage Priming Is Linked To Erna, Brg1’S At-Hook, And Swi/Snf Recruitment, Dhurjhoti Saha, Srinivas Animireddy, Junwoo Lee, Anna Thommen, Mckenzie M Murvin, Yue Lu, J Mauro Calabrese, Blaine Bartholomew

Faculty, Staff and Student Publications

RNA transcribed from enhancers, i.e., eRNA, has been suggested to directly activate transcription by recruiting transcription factors and co-activators. Although there have been specific examples of eRNA functioning in this way, it is not clear how general this may be. We find that the AT-hook of SWI/SNF preferentially binds RNA and, as part of the esBAF complex, associates with eRNA transcribed from intronic and intergenic regions. Our data suggest that SWI/SNF is globally recruited in cis by eRNA to cell-type-specific enhancers, representative of two distinct stages that mimic early mammalian development, and not at enhancers that are shared between the …

Brg1/Brm Inhibitor Targets Aml Stem Cells And Exerts Superior Preclinical Efficacy Combined With Bet Or Menin Inhibitor, Warren Fiskus, Jessica Piel, Mike Collins, Murphy Hentemann, Branko Cuglievan, Christopher P Mill, Christine E Birdwell, Kaberi Das, John A Davis, Hanxi Hou, Antrix Jain, Anna Malovannaya, Tapan M Kadia, Naval Daver, Koji Sasaki, Koichi Takahashi, Danielle Hammond, Patrick K Reville, Jian Wang, Sanam Loghavi, Rwik Sen, Xinjia Ruan, Xiaoping Su, Lauren B Flores, Courtney D Dinardo, Kapil N Bhalla

Faculty, Staff and Student Publications

BRG1 (SMARCA4) and BRM (SMARCA2) are the mutually exclusive core ATPases of the chromatin remodeling BAF (BRG1/BRM-associated factor) complexes. They enable transcription factors/cofactors to access enhancers/promoter and modulate gene expressions responsible for cell growth and differentiation of acute myeloid leukemia (AML) stem/progenitor cells. In AML with MLL1 rearrangement (MLL1r) or mutant NPM1 (mtNPM1), although menin inhibitor (MI) treatment induces clinical remissions, most patients either fail to respond or relapse, some harboring menin mutations. FHD-286 is an orally bioavailable, selective inhibitor of BRG1/BRM under clinical development in AML. Present studies show that FHD-286 induces differentiation and lethality in AML cells with …

Data Mining For Second Malignancies After Car-T, Helen E Heslop

Faculty, Staff and Students Publications

No abstract provided.