Genetic Phenomena Commons^™

Excess Risk Of Chronic Health Conditions In Hispanic Survivors Of Adolescent And Young Adult Cancers, Amy M Berkman, Eunju Choi, John M Salsman, Susan K Peterson, Christabel K Cheung, Clark R Andersen, Qian Lu, J A Livingston, Michelle A T Hildebrandt, Susan K Parsons, Michael E Roth

Faculty, Staff and Student Publications

Purpose: There is a growing population of survivors of adolescent and young adult (AYA) cancers (age 15-39 years at diagnosis). Studies in AYA cancer survivors have identified racial and ethnic disparities in long-term outcomes. To understand the extent to which a cancer diagnosis exacerbates pre-existent health disparities within a minoritized population, comparisons should be made to those of the same race or ethnicity without a cancer history.

Methods: Self-reported data from the National Health Interview Survey (2009-2018) were used to identify Hispanic AYA cancer survivors and Hispanic age- and sex-matched controls. SES factors (marital status, income, education, insurance) and prevalence …

Contemporary Approach To Neurofibromatosis Type 1-Associated Malignant Peripheral Nerve Sheath Tumors, Angela C Hirbe, Carina A Dehner, Eva Dombi, Vanessa Eulo, Andrea M Gross, Taylor Sundby, Alexander J Lazar, Brigitte C Widemann

Faculty, Staff and Student Publications

Most malignant peripheral nerve sheath tumors (MPNSTs) are clinically aggressive high-grade sarcomas, arising in individuals with neurofibromatosis type 1 (NF1) at a significantly elevated estimated lifetime frequency of 8%-13%. In the setting of NF1, MPNSTs arise from malignant transformation of benign plexiform neurofibroma and borderline atypical neurofibromas. Composed of neoplastic cells from the Schwannian lineage, these cancers recur in approximately 50% of individuals, and most patients die within five years of diagnosis, despite surgical resection, radiation, and chemotherapy. Treatment for metastatic disease is limited to cytotoxic chemotherapy and investigational clinical trials. In this article, we review the pathophysiology of this …

Statistical And Practical Considerations In Planning And Conduct Of Dose-Optimization Trials, Ying Yuan, Heng Zhou, Suyu Liu

Faculty, Staff and Student Publications

The U.S. Food and Drug Administration launched Project Optimus with the aim of shifting the paradigm of dose-finding and selection toward identifying the optimal biological dose that offers the best balance between benefit and risk, rather than the maximum tolerated dose. However, achieving dose optimization is a challenging task that involves a variety of factors and is considerably more complicated than identifying the maximum tolerated dose, both in terms of design and implementation. This article provides a comprehensive review of various design strategies for dose-optimization trials, including phase 1/2 and 2/3 designs, and highlights their respective advantages and disadvantages. In …

A Comprehensive Investigation Of The Performance Of A Commercial Scintillator System For Applications In Electron Flash Radiotherapy, Kevin Liu, Shannon Holmes, Emil Schüler, Sam Beddar

Faculty, Staff and Student Publications

Background: Dosimetry in ultra-high dose rate (UHDR) beamlines is significantly challenged by limitations in real-time monitoring and accurate measurement of beam output, beam parameters, and delivered doses using conventional radiation detectors, which exhibit dependencies in ultra-high dose-rate (UHDR) and high dose-per-pulse (DPP) beamline conditions.

Purpose: In this study, we characterized the response of the Exradin W2 plastic scintillator (Standard Imaging, Inc.), a water-equivalent detector that provides measurements with a time resolution of 100 Hz, to determine its feasibility for use in UHDR electron beamlines.

Methods: The W2 scintillator was exposed to an UHDR electron beam with different beam parameters by …

Consolidation Osimertinib Versus Durvalumab Versus Observation After Concurrent Chemoradiation In Unresectable Egfr-Mutant Nsclc: A Multicenter Retrospective Cohort Study, Amin H Nassar, So Yeon Kim, Jacqueline V Aredo, Jamie Feng, Frances Shepherd, Chao Xu, David Kaldas, Jhanelle E Gray, Thomas J Dilling, Joel W Neal, Heather A Wakelee, Yufei Liu, Steven H Lin, Tariq Abuali, Arya Amini, Yunan Nie, Tejas Patil, Anastasiya Lobachov, Jair Bar, Bailey Fitzgerald, Yu Fujiwara, Thomas U Marron, Rohit Thummalapalli, Helena Yu, Dwight H Owen, John Sharp, Saira Farid, Pedro Rocha, Edurne Arriola, Angelica D'Aiello, Haiying Cheng, Ryan Whitaker, Kaushal Parikh, Yash Ashara, Luxi Chen, Kamya Sankar, Jeremy P Harris, Misako Nagasaka, Adanma Ayanambakkam, Ana I Velazquez, Meera Ragavan, Jessica J Lin, Zofia Piotrowska, Molly Wilgucki, Joshua Reuss, Heike Luders, Christian Grohe, Javier Baena Espinar, Ella Feiner, Salman R Punekar, Shruti Gupta, Ticiana Leal, David J Kwiatkowski, Raymond H Mak, Elio Adib, Abdul Rafeh Naqash, Sarah B Goldberg

Faculty, Staff and Student Publications

Introduction: Durvalumab improves survival when used as consolidation therapy after chemoradiation (CRT) in patients with stage III NSCLC. The optimal consolidation therapy for patients with EGFR-mutant (EGFRmut) stage III NSCLC remains unknown.

Methods: In this multi-institutional, international retrospective analysis across 24 institutions, we evaluated outcomes in patients with stage III EGFRmut NSCLC treated with concurrent CRT followed by consolidation therapy with osimertinib, durvalumab, or observation between 2015 and 2022. Kaplan-Meier method was used to estimate real-world progression-free survival (rwPFS, primary end point) and overall survival (secondary end point). Treatment-related adverse events (trAEs) during consolidation treatment were defined using Common Terminology …

Presentation, Management, And Outcomes Of Norovirus In Adult And Pediatric Solid Organ And Hematopoietic Stem Cell Transplant Recipients: A Multicenter, Retrospective Study, Michelle Callegari, Lara A Danziger-Isakov, Anne Rose, Daniel Kaul, Kelly Shaffer, Pearlie P Chong, Diana Florescu, Kaci German, Robin Avery, M Hong Nguyen, Brett Wildfeuer, Marian G Michaels, Michael Green, Kexin Guo, Lihui Zhao, Amna Daud, Michael G Ison

Faculty, Staff and Student Publications

Background: Norovirus (NoV) can cause chronic relapsing and remitting diarrhea in immunocompromised patients. Few multicenter studies have described the clinical course, outcomes, and complications of chronic NoV in transplant recipients.

Methods: A multicenter retrospective study of adult and pediatric SOT and HSCT recipients diagnosed with NoV between November 1, 2017, and February 28, 2021. Data were obtained from electronic medical records (EMR) and entered into a central REDCap database. Descriptive statistics were calculated.

Results: A total of 280 NoV+ patients were identified across eight sites. The majority were adults (74.1%) and SOT recipients (91.4%). Initial diagnosis of NoV occurred a …

Mortality In Recipients Of Allogeneic Haematopoietic Cell Transplantation In The Era Of Cytomegalovirus Primary Prophylaxis: A Single-Centre Retrospective Experience, Anthony Febres-Aldana, Fareed Khawaja, Oscar Morado-Aramburo, Terri Lynn Shigle, Gabriela Rondon, Joseph Sassine, Amy Spallone, Krithika Srinivasan, Jeremy Ramdial, Amin Alousi, Richard Champlin, George Chen, May Daher, Katayoun Rezvani, Ella J Ariza-Heredia, Elizabeth J Shpall, Roy F Chemaly

Faculty, Staff and Student Publications

Objectives: Allogeneic haematopoietic cell transplant (allo-HCT) recipients who are cytomegalovirus (CMV)-seronegative have better post-transplant outcomes than CMV-seropositive recipients. Letermovir (LTV) is approved for CMV primary prophylaxis in adults who are CMV-seropositive after allo-HCT, and its use is associated with improved long-term post-transplant outcomes. We analysed whether LTV has affected the relationship between CMV serostatus and post-transplant outcomes.

Methods: We conducted a retrospective single-centre cohort study of allo-HCT recipients, stratified according to donor (D) and recipient (R). CMV serostatus and the use of LTV: D-/R-, R+/LTV-, and R+/LTV+. Outcomes measured were all-cause and non-relapse mortality, clinically significant CMV infection, graft-versus-host disease, …

Immune Infiltration At The Primary Tumor Is Associated With Clinical Outcome Of Patients With Extranodal Extension Of Lymph Node Metastasis In Oral Cancer, Chieko Michikawa, Frederico O Gleber-Netto, Curtis R Pickering, Xiayu Rao, Jing Wang, Andrew G Sikora, Jeffrey N Myers, Mitchell J Frederick

Faculty, Staff and Student Publications

Background: Extranodal extension (ENE) of lymph node metastasis is one of the most reliable prognostic indicators for patients with locally advanced oral cancer. Although multiple reports have found a close relationship between immune infiltration of tumors and patient clinical outcomes, its association with ENE is unknown.

Methods: We identified 234 human papillomavirus-negative (HPV-) oral cavity squamous cell carcinoma (OSCC) patients in The Cancer Genome Atlas and investigated the immune infiltration profiles of primary tumors and their association with survival.

Results: Hierarchical clustering analysis clearly classified the overall immune infiltration status in OSCC into high immune or low immune groups. The …

Purkinje Cell Dysfunction Causes Disrupted Sleep In Ataxic Mice, Luis E Salazar Leon, Amanda M Brown, Heet Kaku, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

Purkinje cell dysfunction disrupts movement and causes disorders such as ataxia. Recent evidence suggests that Purkinje cell dysfunction may also alter sleep regulation. Here, we used an ataxic mouse model generated by silencing Purkinje cell neurotransmission (L7Cre;Vgatfx/fx) to better understand how cerebellar dysfunction impacts sleep physiology. We focused our analysis on sleep architecture and electrocorticography (ECoG) patterns based on their relevance to extracting physiological measurements during sleep. We found that circadian activity was unaltered in the mutant mice, although their sleep parameters and ECoG patterns were modified. The L7Cre;Vgatfx/fx mutant mice had decreased wakefulness and rapid eye movement (REM) sleep, …

Generation Of A Humanized Mace2 And A Conditional Hace2 Mouse Models Permissive To Sars-Cov-2 Infection, I-Wen Song, Megan Washington, Carolina Leynes, Jason Hsu, Kempaiah Rayavara, Yangjin Bae, Nele Haelterman, Yuqing Chen, Ming-Ming Jiang, Aleksandra Drelich, Vivian Tat, Denise G Lanza, Isabel Lorenzo, Jason D Heaney, Chien-Te Kent Tseng, Brendan Lee, Ronit Marom

Faculty, Staff and Students Publications

The Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) remains a public health concern and a subject of active research effort. Development of pre-clinical animal models is critical to study viral-host interaction, tissue tropism, disease mechanisms, therapeutic approaches, and long-term sequelae of infection. Here, we report two mouse models for studying SARS-CoV-2: A knock-in mAce2F83Y,H353K mouse that expresses a mouse-human hybrid form of the angiotensin-converting enzyme 2 (ACE2) receptor under the endogenous mouse Ace2 promoter, and a Rosa26 conditional knock-in mouse carrying the human ACE2 allele (Rosa26hACE2). Although the mAce2F83Y,H353K mice were susceptible to …

Unveiling Microbial Diversity: Harnessing Long-Read Sequencing Technology, Daniel P Agustinho, Yilei Fu, Vipin K Menon, Ginger A Metcalf, Todd J Treangen, Fritz J Sedlazeck

Faculty, Staff and Students Publications

Long-read sequencing has recently transformed metagenomics, enhancing strain-level pathogen characterization, enabling accurate and complete metagenome-assembled genomes, and improving microbiome taxonomic classification and profiling. These advancements are not only due to improvements in sequencing accuracy, but also happening across rapidly changing analysis methods. In this Review, we explore long-read sequencing's profound impact on metagenomics, focusing on computational pipelines for genome assembly, taxonomic characterization and variant detection, to summarize recent advancements in the field and provide an overview of available analytical methods to fully leverage long reads. We provide insights into the advantages and disadvantages of long reads over short reads and …

Genetic Evaluation For Monogenic Disorders Of Low Bone Mass And Increased Bone Fragility: What Clinicians Need To Know, Emily Busse, Brendan Lee, Sandesh C S Nagamani

Faculty, Staff and Students Publications

Purpose of review: The purpose of this review is to outline the principles of clinical genetic testing and to provide practical guidance to clinicians in navigating genetic testing for patients with suspected monogenic forms of osteoporosis.

Recent findings: Heritability assessments and genome-wide association studies have clearly shown the significant contributions of genetic variations to the pathogenesis of osteoporosis. Currently, over 50 monogenic disorders that present primarily with low bone mass and increased risk of fractures have been described. The widespread availability of clinical genetic testing offers a valuable opportunity to correctly diagnose individuals with monogenic forms of osteoporosis, thus instituting …

Expanding The Phenotype Of Ppp1r21-Related Neurodevelopmental Disorder, Mohammed Almannai, Dana Marafi, Maha S Zaki, Reza Maroofian, Stephanie Efthymiou, Nebal Waill Saadi, Bilal Filimban, Hormos Salimi Dafsari, Fatima Rahman, Shazia Maqbool, Eissa Faqeih, Fuad Al Mutairi, Hind Alsharhan, Omar Abdelaty, Saadoun Bin-Hasan, Ruizhi Duan, Mahmoud M Noureldeen, Alaa Alqattan, Henry Houlden, Jill V Hunter, Jennifer E Posey, James R Lupski, Ayman W El-Hattab

Faculty, Staff and Students Publications

PPP1R21 encodes for a conserved protein that is involved in endosomal maturation. Biallelic pathogenic variants in PPP1R21 have been associated with a syndromic neurodevelopmental disorder from studying 13 affected individuals. In this report, we present 11 additional individuals from nine unrelated families and their clinical, radiological, and molecular findings. We identified eight different variants in PPP1R21, of which six were novel variants. Global developmental delay and hypotonia are neurological features that were observed in all individuals. There is also a similar pattern of dysmorphic features with coarse faces as a gestalt observed in several individuals. Common findings in 75% of …

Improving Access To Exome Sequencing In A Medically Underserved Population Through The Texome Project, Blake Vuocolo, Ryan J German, Seema R Lalani, Chaya N Murali, Carlos A Bacino, Stephanie Baskin, Rebecca Littlejohn, John D Odom, Scott Mclean, Carrie Schmid, Morgan Nutter, Melissa Stuebben, Emily Magness, Olivia Juarez, Dina El Achi, Bailey Mitchell, Kevin E Glinton, Laurie Robak, Sandesh C S Nagamani, Lisa Saba, Adasia Ritenour, Lilei Zhang, Haley Streff, Katie Chan, K Jordan Kemere, Kent Carter, Texome Project, Nichole Owen, Liesbeth Vossaert, Pengfei Liu, Hugo Bellen, Michael F Wangler

Faculty, Staff and Students Publications

PURPOSE: Genomic medicine can end diagnostic odysseys for patients with complex phenotypes; however, limitations in insurance coverage and other systemic barriers preclude individuals from accessing comprehensive genetics evaluation and testing.

METHODS: The Texome Project is a 4-year study that reduces barriers to genomic testing for individuals from underserved and underrepresented populations. Participants with undiagnosed, rare diseases who have financial barriers to obtaining exome sequencing (ES) clinically are enrolled in the Texome Project.

RESULTS: We highlight the Texome Project process and describe the outcomes of the first 60 ES results for study participants. Participants received a genetic evaluation, ES, and return …

Two Genome-Wide Interaction Loci Modify The Association Of Nonsteroidal Anti-Inflammatory Drugs With Colorectal Cancer, David A Drew, Andre E Kim, Yi Lin, Conghui Qu, John Morrison, Juan Pablo Lewinger, Eric Kawaguchi, Jun Wang, Yubo Fu, Natalia Zemlianskaia, Virginia Díez-Obrero, Stephanie A Bien, Niki Dimou, Demetrius Albanes, James W Baurley, Anna H Wu, Daniel D Buchanan, John D Potter, Ross L Prentice, Sophia Harlid, Volker Arndt, Elizabeth L Barry, Sonja I Berndt, Emmanouil Bouras, Hermann Brenner, Arif Budiarto, Andrea Burnett-Hartman, Peter T Campbell, Robert Carreras-Torres, Graham Casey, Jenny Chang-Claude, David V Conti, Matthew A M Devall, Jane C Figueiredo, Stephen B Gruber, Andrea Gsur, Marc J Gunter, Tabitha A Harrison, Akihisa Hidaka, Michael Hoffmeister, Jeroen R Huyghe, Mark A Jenkins, Kristina M Jordahl, Anshul Kundaje, Loic Le Marchand, Li Li, Brigid M Lynch, Neil Murphy, Rami Nassir, Polly A Newcomb, Christina C Newton, Mireia Obón-Santacana, Shuji Ogino, Jennifer Ose, Rish K Pai, Julie R Palmer, Nikos Papadimitriou, Bens Pardamean, Andrew J Pellatt, Anita R Peoples, Elizabeth A Platz, Gad Rennert, Edward Ruiz-Narvaez, Lori C Sakoda, Peter C Scacheri, Stephanie L Schmit, Robert E Schoen, Mariana C Stern, Yu-Ru Su, Duncan C Thomas, Yu Tian, Konstantinos K Tsilidis, Cornelia M Ulrich, Caroline Y Um, Fränzel J B Van Duijnhoven, Bethany Van Guelpen, Emily White, Li Hsu, Victor Moreno, Ulrike Peters, Andrew T Chan, W James Gauderman

Faculty, Staff and Student Publications

Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit

Nivolumab Plus Relatlimab In Patients With Previously Treated Microsatellite Instability-High/Mismatch Repair-Deficient Metastatic Colorectal Cancer: The Phase Ii Checkmate 142 Study, Michael J Overman, Fabio Gelsomino, Massimo Aglietta, Mark Wong, Maria Luisa Limon Miron, Gregory Leonard, Pilar García-Alfonso, Andrew G Hill, Antonio Cubillo Gracian, Eric Van Cutsem, Bassel El-Rayes, Stephen M Mccraith, Beilei He, Ming Lei, Sara Lonardi

Faculty, Staff and Student Publications

BACKGROUND: Programmed death-1 (PD-1) inhibitors, including nivolumab, have demonstrated long-term survival benefit in previously treated patients with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (CRC). PD-1 and lymphocyte-activation gene 3 (LAG-3) are distinct immune checkpoints that are often co-expressed on tumor-infiltrating lymphocytes and contribute to tumor-mediated T-cell dysfunction. Relatlimab is a LAG-3 inhibitor that has demonstrated efficacy in combination with nivolumab in patients with melanoma. Here, we present the results from patients with MSI-H/dMMR metastatic CRC treated with nivolumab plus relatlimab in the CheckMate 142 study.

METHODS: In this open-label, phase II study, previously treated patients with MSI-H/dMMR metastatic CRC …

Smoking Cessation After Initial Treatment Failure With Varenicline Or Nicotine Replacement: A Randomized Clinical Trial, Paul M Cinciripini, Charles E Green, Sanjay Shete, Jennifer A Minnix, Jason D Robinson, Yong Cui, Seokhun Kim, George Kypriotakis, Diane Beneventi, Janice A Blalock, Francesco Versace, Maher Karam-Hage

Faculty, Staff and Student Publications

Importance: Most people who smoke do not quit on their initial attempt.

Objective: To determine the best subsequent strategy for nonabstinence following initial treatment with varenicline or combined nicotine replacement therapy (CNRT).

Design, setting, and participants: Using a double-blind, placebo-controlled, sequential multiple assignment randomized trial, 490 volunteers were randomized to receive 6 weeks of varenicline or CNRT. After 6 weeks, nonabstainers were rerandomized to continue, switch, or increase medication dosage for 6 additional weeks. The study was conducted from June 2015 through October 2019 in a Texas tobacco treatment clinic.

Interventions: The initial treatment was 2 mg/d of varenicline or …

Differentiation Syndrome Associated With Treatment With Idh2 Inhibitor Enasidenib: Pooled Analysis From Clinical Trials, Pau Montesinos, Amir T Fathi, Stéphane De Botton, Eytan M Stein, Amer M Zeidan, Yue Zhu, Thomas Prebet, Carlos E Vigil, Iryna Bluemmert, Xin Yu, Courtney D Dinardo

Faculty, Staff and Student Publications

Treatment with enasidenib, a selective mutant isocitrate dehydrogenase isoform 2 (IDH2) inhibitor, has been associated with the development of differentiation syndrome (DS) in patients with acute myeloid leukemia (AML). Studies on the incidence and clinical features of DS are limited in this setting, and diagnosis is challenging because of nonspecific symptoms. This study assessed the incidence, diagnostic criteria, risk factors, and correlation with clinical response of DS based on the pooled analysis of 4 clinical trials in patients with IDH2-mutated AML treated with enasidenib as monotherapy, or in combination with azacitidine or with chemotherapy. Across the total AML population, 67 …

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 …

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 …

An Unexpected Path For Malat1 In Neurons: Trafficking Out Of The Nucleus For Translation, Bradley W Wright, Jeremy E Wilusz

Faculty, Staff and Students Publications

The Malat1 (metastasis-associated lung adenocarcinoma transcript 1) long noncoding RNA is highly and broadly expressed in mammalian tissues, accumulating in the nucleus where it modulates expression and pre-mRNA processing of many protein-coding genes. In this issue of Genes & Development, Xiao and colleagues (doi:10.1101/gad.351557.124) report that a significant fraction of Malat1 transcripts in cultured mouse neurons are surprisingly exported from the nucleus. These transcripts are packaged with Staufen proteins in RNA granules and traffic down the lengths of neurites. They then can be released in a stimulus-dependent manner to be locally translated into a microprotein that alters neuronal gene …

Empowering Personalized Pharmacogenomics With Generative Ai Solutions, Mullai Murugan, Bo Yuan, Eric Venner, Christie M Ballantyne, Katherine M Robinson, James C Coons, Liwen Wang, Philip E Empey, Richard A Gibbs

Faculty, Staff and Students Publications

Objective: This study evaluates an AI assistant developed using OpenAI's GPT-4 for interpreting pharmacogenomic (PGx) testing results, aiming to improve decision-making and knowledge sharing in clinical genetics and to enhance patient care with equitable access.

Materials and methods: The AI assistant employs retrieval-augmented generation (RAG), which combines retrieval and generative techniques, by harnessing a knowledge base (KB) that comprises data from the Clinical Pharmacogenetics Implementation Consortium (CPIC). It uses context-aware GPT-4 to generate tailored responses to user queries from this KB, further refined through prompt engineering and guardrails.

Results: Evaluated against a specialized PGx question catalog, the AI assistant showed …

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 …

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 …

Localization Of Rnas To The Mitochondria-Mechanisms And Functions, Surbhi Sharma, Furqan M Fazal

Faculty, Staff and Students Publications

The mammalian mitochondrial proteome comprises over 1000 proteins, with the majority translated from nuclear-encoded messenger RNAs (mRNAs). Mounting evidence suggests many of these mRNAs are localized to the outer mitochondrial membrane (OMM) in a pre- or cotranslational state. Upon reaching the mitochondrial surface, these mRNAs are locally translated to produce proteins that are cotranslationally imported into mitochondria. Here, we summarize various mechanisms cells use to localize RNAs, including transfer RNAs (tRNAs), to the OMM and recent technological advancements in the field to study these processes. While most early studies in the field were carried out in yeast, recent studies reveal …

Accelerated Somatic Mutation Calling For Whole-Genome And Whole-Exome Sequencing Data From Heterogenous Tumor Samples, Shuangxi Ji, Tong Zhu, Ankit Sethia, Wenyi Wang

Faculty, Staff and Student Publications

Accurate detection of somatic mutations in DNA sequencing data is a fundamental prerequisite for cancer research. Previous analytical challenges were overcome by consensus mutation calling from four to five popular callers. This, however, increases the already nontrivial computing time from individual callers. Here, we launch MuSE 2, powered by multistep parallelization and efficient memory allocation, to resolve the computing time bottleneck. MuSE 2 speeds up 50 times more than MuSE 1 and eight to 80 times more than other popular callers. Our benchmark study suggests combining MuSE 2 and the recently accelerated Strelka2 achieves high efficiency and accuracy in analyzing …