Digital Commons Network^™

Case-Case Genome-Wide Analyses Identify Subtype-Informative Variants That Confer Risk For Breast Cancer, Xiaohui Sun, Shiv P Verma, Guochong Jia, Xinjun Wang, Jie Ping, Xingyi Guo, Xiao-Ou Shu, Jianhong Chen, Andriy Derkach, Qiuyin Cai, Xiaolin Liang, Jirong Long, Kenneth Offit, Jung H Oh, Anne S Reiner, Gordon P Watt, Meghan Woods, Yaohua Yang, Christine B Ambrosone, Stefan Ambs, Yu Chen, Patrick Concannon, Montserrat Garcia-Closas, Jian Gu, Christopher A Haiman, Jennifer J Hu, Dezheng Huo, Esther M John, Julia A Knight, Christopher I Li, Charles F Lynch, Lene Mellemkjær, Katherine L Nathanson, Barbara Nemesure, Olufunmilayo I Olopade, Andrew F Olshan, Tuya Pal, Julie R Palmer, Michael F Press, Maureen Sanderson, Dale P Sandler, Melissa A Troester, Wei Zheng, Jonine L Bernstein, Matthew F Buas, Xiang Shu

Faculty, Staff and Student Publications

Breast cancer includes several subtypes with distinct characteristic biological, pathologic, and clinical features. Elucidating subtype-specific genetic etiology could provide insights into the heterogeneity of breast cancer to facilitate the development of improved prevention and treatment approaches. In this study, we conducted pairwise case-case comparisons among five breast cancer subtypes by applying a case-case genome-wide association study (CC-GWAS) approach to summary statistics data of the Breast Cancer Association Consortium. The approach identified 13 statistically significant loci and eight suggestive loci, the majority of which were identified from comparisons between triple-negative breast cancer (TNBC) and luminal A breast cancer. Associations of lead …

A 3d Dual-Echo Spiral Sequence For Simultaneous Dynamic Susceptibility Contrast And Dynamic Contrast-Enhanced Mri With Single Bolus Injection, Zhiqiang Li, Dinghui Wang, Melvyn B Ooi, Poonam Choudhary, Sudarshan Ragunathan, John P Karis, James G Pipe, C Chad Quarles, Ashley M Stokes

Faculty, Staff and Student Publications

Purpose: Perfusion MRI reveals important tumor physiological and pathophysiologic information, making it a critical component in managing brain tumor patients. This study aimed to develop a dual-echo 3D spiral technique with a single-bolus scheme to simultaneously acquire both dynamic susceptibility contrast (DSC) and dynamic contrast-enhanced (DCE) data and overcome the limitations of current EPI-based techniques.

Methods: A 3D spiral-based technique with dual-echo acquisition was implemented and optimized on a 3T MRI scanner with a spiral staircase trajectory and through-plane SENSE acceleration for improved speed and image quality, in-plane variable-density undersampling combined with a sliding-window acquisition and reconstruction approach for increased …

Pharmacodynamic Activity Of [18f]-Fluorthanatrace Poly(Adp-Ribose) Polymerase Positron Emission Tomography In Patients With Brca1/2-Mutated Breast Cancer Receiving Talazoparib, Lilie L Lin, Franklin Wong, Ruitao Lin, Timothy Yap, Jennifer K Litton

Faculty, Staff and Student Publications

Purpose: We tested the ability of [18F] fluorthanatrace (FTT), a radiolabeled analog of poly(ADP-ribose) polymerase (PARP)-1 inhibitors, to demonstrate target engagement on positron emission tomography (PET) scans from patients with newly diagnosed primary breast cancer receiving the PARP inhibitor (PARPi) talazoparib.

Methods: Seven patients with germline BRCA1/2 pathogenic variants underwent [18F]FTT PET-computed tomography scanning at baseline, and five underwent repeat scanning 14 days after talazoparib initiation. Maximum uptake on PET was quantified in the primary tumor, involved nodes, contralateral pectoralis muscle, and lumbar vertebra body level 3, and compared between the two time points.

Results: Blocking of [18F]FTT was observed …

A Rare Case Of Fabry's Disease-Induced Cardiomyopathy: A Case Report And Review Of The Literature, Ahmed Hussein, Aya Salih, Yousif Mohamed, Emma Thames, L Maximilian Buja

Faculty, Staff and Student Publications

Fabry's disease, also known as Anderson-Fabry Disease (AFD), is caused by mutations in the α galactosidase A (α GalA) gene found on the X chromosome. This condition results in an accumulation of sphingolipids, including globotriaosylceramide (Gb3), in cells throughout the body. The main effects of Fabry disease typically involve heart, kidney, and nervous system complications. A common cardiac dysfunction is left ventricular hypertrophy. In this case study, we share findings about cardiomyopathy resulting from Fabry disease to explain how this condition impacts the heart and the importance of a biopsy in making a diagnosis. A 57-year-old woman with end-stage renal …

Molecular Pathways And Cellular Subsets Associated With Adverse Clinical Outcomes In Overlapping Immune-Related Myocarditis And Myositis, Bilal A Siddiqui, Nicolas L Palaskas, Sreyashi Basu, Yibo Dai, Zhong He, Shalini S Yadav, James P Allison, Rahul A Sheth, Sudhakar Tummala, Maximilian Buja, Meenakshi B Bhattacharjee, Cezar Iliescu, Anishia Rawther-Karedath, Anita Deswal, Linghua Wang, Padmanee Sharma, Sumit K Subudhi

Faculty, Staff and Student Publications

Immune checkpoint therapies (ICT) can induce life-threatening immune-related adverse events, including myocarditis and myositis, which are rare but often concurrent. The molecular pathways and immune subsets underlying these toxicities remain poorly understood. To address this need, we performed single-cell RNA sequencing of heart and skeletal muscle biopsies obtained from living patients with cancers treated with ICTs and admitted to the hospital with myocarditis and/or myositis (overlapping myocarditis plus myositis, n = 10; myocarditis-only, n = 1) or ICT-exposed patients ruled out for toxicity utilized as controls (n = 9). All biopsies were obtained within 96 hours of clinical presentation. Analyses …

A Randomised, Parallel-Group, Double-Blind, Placebo-Controlled Phase 3 Study To Determine The Effectiveness Of The Type I Interferon Receptor Antibody, Anifrolumab, In Systemic Sclerosis: Daisy Study Design And Rationale, Dinesh Khanna, Christopher P Denton, Shervin Assassi, Masataka Kuwana, Yannick Allanore, Robyn T Domsic, Christi Kleoudis, John Xu, Eszter Csomor, Caroline Seo, Marius Albulescu, Raj Tummala, Hussein Al-Mossawi, Rubana N Kalyani, Francesco Del Galdo

Faculty, Staff and Student Publications

Objectives: The type I interferon pathway is a promising target for treatment of patients with systemic sclerosis (SSc). Here, we describe the design of a multinational, randomised phase 3 study to Determine the effectiveness of the type I interferon receptor antibody, Anifrolumab, In SYstemic sclerosis (DAISY).

Methods: DAISY includes a 52-week double-blind, placebo-controlled treatment period, a 52-week open-label active treatment period, and a 12-week safety follow-up period. The patient population includes a planned 306 adults with limited or diffuse cutaneous active SSc who satisfied American College of Rheumatology/European Alliance of Associations for Rheumatology 2013 SSc criteria. Use of standard immunosuppressants, …

Enolase Inhibitors As Therapeutic Leads For Naegleria Fowleri Infection, Jillian E Milanes, Victoria C Yan, Cong-Dat Pham, Florian Muller, Samuel Kwain, Kerrick C Rees, Brian N Dominy, Daniel C Whitehead, Steven W Millward, Madison Bolejack, Roger Shek, Logan Tillery, Isabelle Q Phan, Bart Staker, E Ashley Moseman, Xiang Zhang, Xipeng Ma, Audriy Jebet, Xinmin Yin, James C Morris

Faculty, Staff and Student Publications

Infections with the pathogenic free-living amoebae Naegleria fowleri can lead to life-threatening illnesses including catastrophic primary amoebic meningoencephalitis (PAM). Efficacious treatment options for these infections are lacking and the mortality rate remains >95% in the US. Glycolysis is very important for the infectious trophozoite lifecycle stage and inhibitors of glucose metabolism have been found to be toxic to the pathogen. Recently, human enolase 2 (ENO2) phosphonate inhibitors have been developed as lead agents to treat glioblastoma multiforme (GBM). These compounds, which cure GBM in a rodent model, are well-tolerated in mammals because enolase 1 (ENO1) is the predominant isoform used …

Nf1 Mutation Disrupts Activity-Dependent Oligodendroglial Plasticity And Motor Learning In Mice, Yuan Pan, Jared D Hysinger, Belgin Yalçın, James J Lennon, Youkyeong Gloria Byun, Preethi Raghavan, Nicole F Schindler, Corina Anastasaki, Jit Chatterjee, Lijun Ni, Haojun Xu, Karen Malacon, Samin M Jahan, Alexis E Ivec, Benjamin E Aghoghovwia, Christopher W Mount, Surya Nagaraja, Suzanne Scheaffer, Laura D Attardi, David H Gutmann, Michelle Monje

Faculty, Staff and Student Publications

Neurogenetic disorders, such as neurofibromatosis type 1 (NF1), can cause cognitive and motor impairments, traditionally attributed to intrinsic neuronal defects such as disruption of synaptic function. Activity-regulated oligodendroglial plasticity also contributes to cognitive and motor functions by tuning neural circuit dynamics. However, the relevance of oligodendroglial plasticity to neurological dysfunction in NF1 is unclear. Here we explore the contribution of oligodendrocyte progenitor cells (OPCs) to pathological features of the NF1 syndrome in mice. Both male and female littermates (4-24 weeks of age) were used equally in this study. We demonstrate that mice with global or OPC-specific Nf1 heterozygosity exhibit defects …

Autophagic Signaling Promotes Systems-Wide Remodeling In Skeletal Muscle Upon Oncometabolic Stress By D2-Hg, Yaqi Gao, Kyoungmin Kim, Heidi Vitrac, Rebecca L Salazar, Benjamin D Gould, Daniel Soedkamp, Weston Spivia, Koen Raedschelders, An Q Dinh, Anna G Guzman, Lin Tan, Stavros Azinas, David J R Taylor, Walter Schiffer, Daniel Mcnavish, Helen B Burks, Roberta A Gottlieb, Philip L Lorenzi, Blake M Hanson, Jennifer E Van Eyk, Heinrich Taegtmeyer, Anja Karlstaedt

Faculty, Staff and Student Publications

OBJECTIVES: Cachexia is a metabolic disorder and comorbidity with cancer and heart failure. The syndrome impacts more than thirty million people worldwide, accounting for 20% of all cancer deaths. In acute myeloid leukemia, somatic mutations of the metabolic enzyme isocitrate dehydrogenase 1 and 2 cause the production of the oncometabolite D2-hydroxyglutarate (D2-HG). Increased production of D2-HG is associated with heart and skeletal muscle atrophy, but the mechanistic links between metabolic and proteomic remodeling remain poorly understood. Therefore, we assessed how oncometabolic stress by D2-HG activates autophagy and drives skeletal muscle loss.

METHODS: We quantified genomic, metabolomic, and proteomic changes in …

Antitumor Activity Of A Novel Lair1 Antagonist In Combination With Anti-Pd1 To Treat Collagen-Rich Solid Tumors, Bertha L Rodriguez, Jiawei Huang, Laura Gibson, Jared J Fradette, Hung-I H Chen, Kikuye Koyano, Czrina Cortez, Betty Li, Carmence Ho, Amir M Ashique, Vicky Y Lin, Suzanne Crawley, Julie M Roda, Peirong Chen, Bin Fan, Jeong Kim, James Sissons, Jonathan Sitrin, Daniel D Kaplan, Don L Gibbons, Lee B Rivera

Faculty, Staff and Student Publications

We recently reported that resistance to PD-1 blockade in a refractory lung cancer-derived model involved increased collagen deposition and the collagen-binding inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR1). Thus, we hypothesized that LAIR1 and collagen cooperated to suppress therapeutic response. In this study, we report that LAIR1 is associated with tumor stroma and is highly expressed by intratumoral myeloid cells in both human tumors and mouse models of cancer. Stroma-associated myeloid cells exhibit a suppressive phenotype and correlate with LAIR1 expression in human cancer. NGM438, a novel humanized LAIR1 antagonist mAb, elicits myeloid inflammation and allogeneic T-cell responses by binding …

Neoantigen-Specific Cytotoxic Tr1 Cd4 T Cells Suppress Cancer Immunotherapy, Hussein Sultan, Yoshiko Takeuchi, Jeffrey P Ward, Naveen Sharma, Tian-Tian Liu, Vladimir Sukhov, Maria Firulyova, Yuang Song, Samuel Ameh, Simone Brioschi, Darya Khantakova, Cora D Arthur, J Michael White, Heather Kohlmiller, Andres M Salazar, Robert Burns, Helio A Costa, Kelly D Moynihan, Yik Andy Yeung, Ivana Djuretic, Ton N Schumacher, Kathleen C F Sheehan, Marco Colonna, James P Allison, Kenneth M Murphy, Maxim N Artyomov, Robert D Schreiber

Faculty, Staff and Student Publications

CD4+ T cells can either enhance or inhibit tumour immunity. Although regulatory T cells have long been known to impede antitumour responses1-5, other CD4+ T cells have recently been implicated in inhibiting this response6,7. Yet, the nature and function of the latter remain unclear. Here, using vaccines containing MHC class I (MHC-I) neoantigens (neoAgs) and different doses of tumour-derived MHC-II neoAgs, we discovered that whereas the inclusion of vaccines with low doses of MHC-II-restricted peptides (LDVax) promoted tumour rejection, vaccines containing high doses of the same MHC-II neoAgs (HDVax) inhibited rejection. Characterization of the inhibitory cells induced by HDVax identified …

Utilising Discriminant Function Analysis (Dfa) For Classifying Osteoarthritis (Oa) Patients And Volunteers Based On Biomarker Concentration, Laura Jane Coleman, John L Byrne, Stuart Edwards, Rosemary O'Hara

Faculty, Staff and Student Publications

Osteoarthritis (OA) is a degenerative joint disease characterised by the breakdown of cartilage, causing pain, stiffness, and limited movement. Early diagnosis is crucial for effective management but remains challenging due to non-specific early symptoms. This study explores the application of Discriminant Function Analysis (DFA) to classify OA patients and healthy volunteers based on biomarker concentrations of Interleukin-6 (IL-6), Tumour necrosis factor-alpha (TNF-α), and Myeloperoxidase (MPO). DFA was employed to analyse biomarker data from 86 participants (58 patients, 28 volunteers) to evaluate the discriminatory power of these biomarkers in predicting OA. Significant differences were observed in MPO and TNF-α levels between …

A Comparison Of Tracheal Intubation Using Direct Laryngoscope And Video Laryngoscope In The Sellick And Trendelenburg Position With That Using Direct Laryngoscope In The Supine Sniffing Position: A Randomized Controlled Trial, Yun-Jeong Chae, Jung-Yoon Moon, Min-Gyu Lee, Han-Bum Joe

Faculty, Staff and Student Publications

Background: Tracheal intubation in the Sellick and Trendelenburg position (ST position) can prevent pulmonary aspiration but increase the difficulty of tracheal intubation. We compared tracheal intubation using video and direct laryngoscopy in the ST position with direct laryngoscopy in the supine sniffing position to evaluate the overall intubation performance. Methods: One hundred and twenty patients were randomly assigned to three groups: direct laryngoscope in the supine sniffing position (control), direct laryngoscope in the ST position (ST direct), and video laryngoscope in the ST position (ST video). The primary outcome was the intubation time; secondary outcomes included the first …

Martian Atmospheric Hydrogen And Deuterium: Seasonal Changes And Paradigm For Escape To Space, John T Clarke, Majd Mayyasi, Dolon Bhattacharyya, Jean-Yves Chaufray, Nicolas Schneider, Bruce Jakosky, Roger Yelle, Franck Montmessin, Michael Chaffin, Shannon Curry, Justin Deighan, Sonal Jain, Jean-Loup Bertaux, Eryn Cangi, Matteo Crismani, Scott Evans, Sumedha Gupta, Franck Lefevre, Greg Holsclaw, Daniel Lo, William Mcclintock, Michael Stevens, Ian Stewart, Shane Stone, Paul Mahaffy, Mehdi Benna, Meredith Elrod

Faculty, Staff and Student Publications

Mars' water history is fundamental to understanding Earth-like planet evolution. Water escapes to space as atoms, and hydrogen atoms escape faster than deuterium giving an increase in the residual D/H ratio. The present ratio reflects the total water Mars has lost. Observations with the Mars Atmosphere and Volatile Evolution (MAVEN) and Hubble Space Telescope (HST) spacecraft provide atomic densities and escape rates for H and D. Large increases near perihelion observed each martian year are consistent with a strong upwelling of water vapor. Short-term changes require processes in addition to thermal escape, likely from atmospheric dynamics and superthermal atoms. Including …

Detection Of Diffusely Abnormal White Matter In Multiple Sclerosis On Multiparametric Brain Mri Using Semi-Supervised Deep Learning, Benjamin C Musall, Refaat E Gabr, Yanyu Yang, Arash Kamali, John A Lincoln, Michael A Jacobs, Vi Ly, Xi Luo, Jerry S Wolinsky, Ponnada A Narayana, Khader M Hasan

Faculty, Staff and Student Publications

In addition to focal lesions, diffusely abnormal white matter (DAWM) is seen on brain MRI of multiple sclerosis (MS) patients and may represent early or distinct disease processes. The role of MRI-observed DAWM is understudied due to a lack of automated assessment methods. Supervised deep learning (DL) methods are highly capable in this domain, but require large sets of labeled data. To overcome this challenge, a DL-based network (DAWM-Net) was trained using semi-supervised learning on a limited set of labeled data for segmentation of DAWM, focal lesions, and normal-appearing brain tissues on multiparametric MRI. DAWM-Net segmentation performance was compared to …

In Silico Analysis Of The Rop29 Protein As A Vaccine Candidate Against Toxoplasma Gondii, Amir Karimipour-Saryazdi, Fatemeh Ghaffarifar, Abdolhossein Dalimi, Masoud Foroutan, John Horton, Javid Sadraei

Faculty, Staff and Student Publications

The progression of Toxoplasma gondii (T. gondii) invasion is aided by rhoptry proteins (ROPs), which are also crucial for the parasite's survival in host cells. In this study, in silico analysis was performed to examine the various aspects of the ROP29 protein, such as physicochemical properties, potential T- and B-cell epitopes, and other significant features. The research revealed that there were 55 possible sites for posttranslational modification in the ROP29 protein. The secondary structure of the ROP29 protein consists of a random coil, an alpha-helix, and an extended strand, which account for 49.69%, 36.81%, and 13.50%, respectively. Moreover, …

Differential Lipid Binding Specificities Of Rap1a And Rap1b Are Encoded By The Amino Acid Sequence Of The Membrane Anchors, Mussie K Araya, Wei Chen, Yuepeng Ke, Yubin Zhou, Alemayehu A Gorfe, John F Hancock, Junchen Liu

Faculty, Staff and Student Publications

RAP1 proteins belong to the RAS family of small GTPases that operate as molecular switches by cycling between GDP-bound inactive and GTP-bound active states. The C-terminal anchors of RAP1 proteins are known to direct membrane localization, but how these anchors organize RAP1 on the plasma membrane (PM) has not been investigated. Using high-resolution imaging, we show that RAP1A and RAP1B form spatially segregated nanoclusters on the inner leaflet of the PM, with further lateral segregation between GDP-bound and GTP-bound proteins. The C-terminal polybasic anchors of RAP1A and RAP1B differ in their amino acid sequences and exhibit different lipid binding specificities, …

A Scaled Proteomic Discovery Study For Prostate Cancer Diagnostic Markers Using Proteograph, Matthew E K Chang, Jane Lange, Jessie May Cartier, Travis W Moore, Sophia M Soriano, Brenna Albracht, Michael Krawitzky, Harendra Guturu, Amir Alavi, Alexey Stukalov, Xiaoyuan Zhou, Eltaher M Elgierari, Jessica Chu, Ryan Benz, Juan C Cuevas, Shadi Ferdosi, Daniel Hornburg, Omid Farokhzad, Asim Siddiqui, Serafim Batzoglou, Robin J Leach, Michael A Liss, Ryan P Kopp, Mark R Flory

Faculty, Staff and Student Publications

There is a significant unmet need for clinical reflex tests that increase the specificity of prostate-specific antigen blood testing, the longstanding but imperfect tool for prostate cancer diagnosis. Towards this endpoint, we present the results from a discovery study that identifies new prostate-specific antigen reflex markers in a large-scale patient serum cohort using differentiating technologies for deep proteomic interrogation. We detect known prostate cancer blood markers as well as novel candidates. Through bioinformatic pathway enrichment and network analysis, we reveal associations of differentially abundant proteins with cytoskeletal, metabolic, and ribosomal activities, all of which have been previously associated with prostate …

Cell-Specific Regulation Of The Circadian Clock By Bmal1 In The Paraventricular Nucleus: Implications For Regulation Of Systemic Biological Rhythms, Rachel Van Drunen, Yulin Dai, Haichao Wei, Baharan Fekry, Sina Noori, Samay Shivshankar, Rafael Bravo, Zhongming Zhao, Seung-Hee Yoo, Nicholas Justice, Jia Qian Wu, Qingchun Tong, Kristin Eckel-Mahan

Faculty, Staff and Student Publications

Circadian rhythms are internal biological rhythms driving temporal tissue-specific, metabolic programs. Loss of the circadian transcription factor BMAL1 in the paraventricular nucleus (PVN) of the hypothalamus reveals its importance in metabolic rhythms, but its functions in individual PVN cells are poorly understood. Here, loss of BMAL1 in the PVN results in arrhythmicity of processes controlling energy balance and alters peripheral diurnal gene expression. BMAL1 chromatin immunoprecipitation sequencing (ChIP-seq) and single-nucleus RNA sequencing (snRNA-seq) reveal its temporal regulation of target genes, including oxytocin (OXT), and restoring circulating OXT peaks in BMAL1-PVN knockout (KO) mice rescues absent activity rhythms. While glutamatergic neurons …

Investigating Gene Functions And Single-Cell Expression Profiles Of De Novo Variants In Orofacial Clefts, Toshiyuki Itai, Fangfang Yan, Andi Liu, Yulin Dai, Chihiro Iwaya, Sarah W Curtis, Elizabeth J Leslie, Lukas M Simon, Peilin Jia, Xiangning Chen, Junichi Iwata, Zhongming Zhao

Faculty, Staff and Student Publications

Orofacial clefts (OFCs) are common congenital birth defects with various etiologies, including genetic variants. Online Mendelian Inheritance in Man (OMIM) annotated several hundred genes involving OFCs. Furthermore, several hundreds of de novo variants (DNVs) have been identified from individuals with OFCs. Some DNVs are related to known OFC genes or pathways, but there are still many DNVs whose relevance to OFC development is unknown. To explore novel gene functions and their cellular expression profiles, we focused on DNVs in genes that were not listed in OMIM. We collected 960 DNVs in 853 genes from published studies and curated these genes, …

Membrane Vectorial Lipidomic Features Of Coral Host Cells’ Plasma Membrane And Lipid Profiles Of Their Endosymbionts Cladocopium, Tatyana V Sikorskaya, Ekaterina V Ermolenko, Taliya T Ginanova, Andrey V Boroda, Kseniya V Efimova, Mikhail Bogdanov

Faculty, Staff and Student Publications

The symbiotic relationships between coral animal host and autotrophic dinoflagellates are based on the mutual exchange and tight control of nutritional inputs supporting successful growth. The corals Sinularia heterospiculata and Acropora aspera were cultivated using a flow-through circulation system supplying seawater during cold and warm seasons of the year, then sorted into host cells and symbionts and subjected to phylogenetic, morphological, and advanced lipid analyses. Here we show, that the lipidomes of the dinoflagellates Cladocopium C1/C3 and acroporide-specific Cladocopium hosted by the corals, are determined by lipidomic features of different thermosensitivity and unique betaine- and phospholipid molecular species. Phosphatidylserines and …

Deepface: Deep-Learning-Based Framework To Contextualize Orofacial-Cleft-Related Variants During Human Embryonic Craniofacial Development, Yulin Dai, Toshiyuki Itai, Guangsheng Pei, Fangfang Yan, Yan Chu, Xiaoqian Jiang, Seth M Weinberg, Nandita Mukhopadhyay, Mary L Marazita, Lukas M Simon, Peilin Jia, Zhongming Zhao

Faculty, Staff and Student Publications

Orofacial clefts (OFCs) are among the most common human congenital birth defects. Previous multiethnic studies have identified dozens of associated loci for both cleft lip with or without cleft palate (CL/P) and cleft palate alone (CP). Although several nearby genes have been highlighted, the "casual" variants are largely unknown. Here, we developed DeepFace, a convolutional neural network model, to assess the functional impact of variants by SNP activity difference (SAD) scores. The DeepFace model is trained with 204 epigenomic assays from crucial human embryonic craniofacial developmental stages of post-conception week (pcw) 4 to pcw 10. The Pearson correlation coefficient between …

Crispr-Cas9 And Cas12a Target Site Richness Reflects Genomic Diversity In Natural Populations Of Anopheles Gambiae And Aedes Aegypti Mosquitoes, Travis C Collier, Yoosook Lee, Derrick K Mathias, Víctor López Del Amo

Faculty, Staff and Student Publications

Due to limitations in conventional disease vector control strategies including the rise of insecticide resistance in natural populations of mosquitoes, genetic control strategies using CRISPR gene drive systems have been under serious consideration. The identification of CRISPR target sites in mosquito populations is a key aspect for developing efficient genetic vector control strategies. While genome-wide Cas9 target sites have been explored in mosquitoes, a precise evaluation of target sites focused on coding sequence (CDS) is lacking. Additionally, target site polymorphisms have not been characterized for other nucleases such as Cas12a, which require a different DNA recognition site (PAM) and would …

Epigenome-Wide Association Study Of Lung Cancer Among Never Smokers In Two Prospective Cohorts In Shanghai, China, Mohammad L Rahman, Charles E Breeze, Xiao-Ou Shu, Jason Y Y Wong, Batel Blechter, Andres Cardenas, Xuting Wang, Bu-Tian Ji, Wei Hu, Qiuyin Cai, H Dean Hosgood, Gong Yang, Jianxin Shi, Jirong Long, Yu-Tang Gao, Douglas A Bell, Wei Zheng, Nathaniel Rothman, Qing Lan

Faculty, Staff and Student Publications

BACKGROUND: The aetiology of lung cancer among individuals who never smoked remains elusive, despite 15% of lung cancer cases in men and 53% in women worldwide being unrelated to smoking. Epigenetic alterations, particularly DNA methylation (DNAm) changes, have emerged as potential drivers. Yet, few prospective epigenome-wide association studies (EWAS), primarily focusing on peripheral blood DNAm with limited representation of never smokers, have been conducted.

METHODS: We conducted a nested case-control study of 80 never-smoking incident lung cancer cases and 83 never-smoking controls within the Shanghai Women's Health Study and Shanghai Men's Health Study. DNAm was measured in prediagnostic oral rinse …

Clear Thrombectomy Score: An Index To Estimate The Probability Of Good Functional Outcome With Or Without Endovascular Treatment In The Late Window For Anterior Circulation Occlusion, James E Siegler, Manisha Koneru, Muhammad M Qureshi, Mohamed Doheim, Raul G Nogueira, Nicolas Martinez-Majander, Simon Nagel, Mary Penckofer, Jelle Demeestere, Volker Puetz, Marc Ribo, Mohamad Abdalkader, João Pedro Marto, Alhamza R Al-Bayati, Hiroshi Yamagami, Diogo C Haussen, Marta Olive-Gadea, Simon Winzer, Mahmoud H Mohammaden, Robin Lemmens, Kanta Tanaka, Pekka Virtanen, Anne Dusart, Flavio Bellante, Daniel P O Kaiser, Francois Caparros, Hilde Henon, João Nuno Ramos, Santiago Ortega-Gutierrez, Sunil A Sheth, Stefania Nannoni, Lieselotte Vandewalle, Johannes Kaesmacher, Sergio Salazar-Marioni, Liisa Tomppo, Rita Ventura, Syed F Zaidi, Mouhammad Jumaa, Alicia C Castonguay, Milagros Galecio-Castillo, Ajit S Puri, Adnan Mujanovic, Piers Klein, Liqi Shu, Behzad Farzin, Hannah Moomey, Hesham E Masoud, Jessica Jesser, Markus A Möhlenbruch, Peter A Ringleb, Daniel Strbian, Osama O Zaidat, Shadi Yaghi, Davide Strambo, Patrik Michel, Daniel Roy, Shinichi Yoshimura, Kazutaka Uchida, Jean Raymond, Thanh N Nguyen

Faculty, Staff and Student Publications

Background: With the expanding eligibility for endovascular therapy (EVT) of patients presenting in the late window (6-24 hours after last known well), we aimed to derive a score to predict favorable outcomes associated with EVT versus best medical management.

Methods and results: A multinational observational cohort of patients from the CLEAR (Computed Tomography for Late Endovascular Reperfusion) study with proximal intracranial occlusion (2014-2022) was queried (n=58 sites). Logistic regression analyses were used to derive a 9-point score for predicting good functional outcome (modified Rankin Scale score 0-2 or return to premorbid modified Rankin Scale score) at 90 days, with sensitivity …

Enhancing The Carbon Monoxide Oxidation Performance Through Surface Defect Enrichment Of Ceria-Based Supports For Platinum Catalyst, Shaohua Xie, Yue Lu, Kailong Ye, Wei Tan, Sufeng Cao, Chunying Wang, Daekun Kim, Xing Zhang, Jeremia Loukusa, Yaobin Li, Yan Zhang, Lu Ma, Steven N Ehrlich, Nebojsa S Marinkovic, Jiguang Deng, Maria Flytzani-Stephanopoulos, Fudong Liu

Faculty, Staff and Student Publications

Effective synthesis and application of single-atom catalysts on supports lacking enough defects remain a significant challenge in environmental catalysis. Herein, we present a universal defect-enrichment strategy to increase the surface defects of CeO2-based supports through H2 reduction pretreatment. The Pt catalysts supported by defective CeO2-based supports, including CeO2, CeZrOx, and CeO2/Al2O3 (CA), exhibit much higher Pt dispersion and CO oxidation activity upon reduction activation compared to their counterpart catalysts without defect enrichment. Specifically, Pt is present as embedded single atoms on the CA support with enriched surface defects (CA-HD) based on which the highly active catalyst showing embedded …

Hiv/Aids-Associated Knowledge And Attitudes Towards Treating Disadvantaged Communities Among Pre-Community-Based Dental Education Dental Students In The Us, Aditi Tomar, Hannah Balcezak, Shirley Lewis Miranda, Marie C Latortue, Richa Chinchkhandi, Lisa Wigfall

Faculty, Staff and Student Publications

This study examines HIV/AIDS-associated knowledge and attitudes towards treating disadvantaged communities among predoctoral dental students in U.S. dental schools who have not yet commenced their Community-Based Dental Education (CBDE) training. It also compares the difference in the knowledge and attitudes between students with reported community engagement with PLWHA and those without. Our study comprised 89 predoctoral dental students within their D1-D3 years of dental school who had not yet initiated their Community-Based Dental Education (referred to as pre-CBDE dental students). Their responses were collected via an online survey. The participants were 68% females, 94% heterosexual, and with a mean age …

Brain-Age Prediction: Systematic Evaluation Of Site Effects, And Sample Age Range And Size, Yuetong Yu, Hao-Qi Cui, Shalaila S Haas, Faye New, Nicole Sanford, Kevin Yu, Denghuang Zhan, Guoyuan Yang, Jia-Hong Gao, Dongtao Wei, Jiang Qiu, Nerisa Banaj, Dorret I Boomsma, Alan Breier, Henry Brodaty, Randy L Buckner, Jan K Buitelaar, Dara M Cannon, Xavier Caseras, Vincent P Clark, Patricia J Conrod, Fabrice Crivello, Eveline A Crone, Udo Dannlowski, Christopher G Davey, Lieuwe De Haan, Greig I De Zubicaray, Annabella Di Giorgio, Lukas Fisch, Simon E Fisher, Barbara Franke, David C Glahn, Dominik Grotegerd, Oliver Gruber, Raquel E Gur, Ruben C Gur, Tim Hahn, Ben J Harrison, Sean Hatton, Ian B Hickie, Hilleke E Hulshoff Pol, Alec J Jamieson, Terry L Jernigan, Jiyang Jiang, Andrew J Kalnin, Sim Kang, Nicole A Kochan, Anna Kraus, Jim Lagopoulos, Luisa Lazaro, Brenna C Mcdonald, Colm Mcdonald, Katie L Mcmahon, Benson Mwangi, Fabrizio Piras, Raul Rodriguez-Cruces, Jessica Royer, Perminder S Sachdev, Theodore D Satterthwaite, Andrew J Saykin, Gunter Schumann, Pierluigi Sevaggi, Jordan W Smoller, Jair C Soares, Gianfranco Spalletta, Christian K Tamnes, Julian N Trollor, Dennis Van't Ent, Daniela Vecchio, Henrik Walter, Yang Wang, Bernd Weber, Wei Wen, Lara M Wierenga, Steven C R Williams, Mon-Ju Wu, Giovana B Zunta-Soares, Boris Bernhardt, Paul Thompson, Sophia Frangou, Ruiyang Ge, Enigma‐Lifespan Working Group

Faculty, Staff and Student Publications

Structural neuroimaging data have been used to compute an estimate of the biological age of the brain (brain‐age) which has been associated with other biologically and behaviorally meaningful measures of brain development and aging. The ongoing research interest in brain‐age has highlighted the need for robust and publicly available brain‐age models pre‐trained on data from large samples of healthy individuals. To address this need we have previously released a developmental brain‐age model. Here we expand this work to develop, empirically validate, and disseminate a pre‐trained brain‐age model to cover most of the human lifespan. To achieve this, we selected the …

Bayesian Varying-Effects Vector Autoregressive Models For Inference Of Brain Connectivity Networks And Covariate Effects In Pediatric Traumatic Brain Injury, Yangfan Ren, Nathan Osborne, Christine B Peterson, Dana M Demaster, Linda Ewing-Cobbs, Marina Vannucci

Faculty, Staff and Student Publications

In this article, we develop an analytical approach for estimating brain connectivity networks that accounts for subject heterogeneity. More specifically, we consider a novel extension of a multi-subject Bayesian vector autoregressive model that estimates group-specific directed brain connectivity networks and accounts for the effects of covariates on the network edges. We adopt a flexible approach, allowing for (possibly) nonlinear effects of the covariates on edge strength via a novel Bayesian nonparametric prior that employs a weighted mixture of Gaussian processes. For posterior inference, we achieve computational scalability by implementing a variational Bayes scheme. Our approach enables simultaneous estimation of group-specific …

Clinical And Genomic Landscape Of Ras Mutations In Gynecologic Cancers, Ji Son, Yingao Zhang, Heather Lin, Oriol Mirallas, Pablo Alvarez Ballesteros, Mirella Nardo, Natalie Clark, R Tyler Hillman, Erick Campbell, Vijaykumar Holla, Amber M Johnson, Amadeo B Biter, Ying Yuan, Lauren P Cobb, David M Gershenson, Amir A Jazaeri, Karen H Lu, Pamela T Soliman, Shannon N Westin, Elizabeth D Euscher, Barrett C Lawson, Richard K Yang, Funda Meric-Bernstam, David S Hong

Faculty, Staff and Student Publications

Purpose: We aimed to describe RAS mutations in gynecologic cancers as they relate to clinicopathologic and genomic features, survival, and therapeutic implications.

Experimental design: Gynecologic cancers with available somatic molecular profiling data at our institution between February 2010 and August 2022 were included and grouped by RAS mutation status. Overall survival was estimated by the Kaplan-Meier method, and multivariable analysis was performed using the Cox proportional hazard model.

Results: Of 3,328 gynecologic cancers, 523 (15.7%) showed any RAS mutation. Patients with RAS-mutated tumors were younger (57 vs. 60 years nonmutated), had a higher prevalence of endometriosis (27.3% vs. 16.9%), and …