Medicine and Health Sciences Commons^™

Difficult To Treat Depression: Focus On Approach, Algorithms, And Access, Jordan F Karp, Roberta D Brinton, Jay C Fournier, Lisa Harding, Manish K Jha, Eric J Lenze, Sanjay J Mathew, Samantha Meltzer-Brody, David C Mohr, Patricio Riva-Posse, Ilse Wiechers, Nolan R Williams

Staff and Researcher Publications

The pandemic refocused interest on the burden of depression across the lifespan; the increased efforts to prevent and treat depression are now a priority of health care systems, insurers, patient advocates, digital therapeutic engineers, telemedicine platforms, and community health agencies. However, the challenges of treating depression to remission in adult patients who do not respond to first, second, or third levels of oral pharmacotherapy remain. The increased prevalence of these conditions is at odds with the shrinking psychiatric workforce. Since addressing difficult to treat depression is situated in a rapidly evolving treatment landscape, The University of Arizona College of Medicine-Tucson …

Using High-Frequency Oscillations From Brief Intraoperative Neural Recordings To Predict The Seizure Onset Zone, Behrang Fazli Besheli, Zhiyi Sha, Jay R Gavvala, Sacit Karamursel, Michael Quach, Chandra Prakash Swamy, Amir Hossein Ayyoubi, Alica M Goldman, Daniel J Curry, Sameer A Sheth, David Darrow, Kai J Miller, David J Francis, Gregory A Worrell, Thomas R Henry, Nuri F Ince

Faculty, Staff and Students Publications

BACKGROUND: While high-frequency oscillations (HFOs) and their stereotyped clusters (sHFOs) have emerged as potential neuro-biomarkers for the rapid localization of the seizure onset zone (SOZ) in epilepsy, their clinical application is hindered by the challenge of automated elimination of pseudo-HFOs originating from artifacts in heavily corrupted intraoperative neural recordings. This limitation has led to a reliance on semi-automated detectors, coupled with manual visual artifact rejection, impeding the translation of findings into clinical practice.

METHODS: In response, we have developed a computational framework that integrates sparse signal processing and ensemble learning to automatically detect genuine HFOs of intracranial EEG data. This …

Space: An Open-Source, Single-Cell Analysis Of Cell Painting Data, Fabio Stossi, Pankaj K Singh, Michela Marini, Kazem Safari, Adam T Szafran, Alejandra Rivera Tostado, Christopher D Candler, Maureen G Mancini, Elina A Mosa, Michael J Bolt, Demetrio Labate, Michael A Mancini

Faculty, Staff and Students Publications

Phenotypic profiling by high throughput microscopy, including Cell Painting, has become a leading tool for screening large sets of perturbations in cellular models. To efficiently analyze this big data, available open-source software requires computational resources usually not available to most laboratories. In addition, the cell-to-cell variation of responses within a population, while collected and analyzed, is usually averaged and unused. We introduce SPACe (Swift Phenotypic Analysis of Cells), an open-source platform for analysis of single-cell image-based morphological profiles produced by Cell Painting. We highlight several advantages of SPACe, including processing speed, accuracy in mechanism of action recognition, reproducibility across biological …

Mitochondrial Heteroplasmy Improves Risk Prediction For Myeloid Neoplasms, Yun Soo Hong, Sergiu Pasca, Wen Shi, Daniela Puiu, Nicole J Lake, Monkol Lek, Meng Ru, Megan L Grove, Anna Prizment, Corinne E Joshu, Elizabeth A Platz, Eliseo Guallar, Dan E Arking, Lukasz P Gondek

Faculty, Staff and Student Publications

Clonal hematopoiesis of indeterminate potential is the primary pathogenic risk factor for myeloid neoplasms, while heteroplasmy (mutations in a subset of cellular mitochondrial DNA) is another marker of clonal expansion associated with hematological malignancies. We explore how these two markers relate and influence myeloid neoplasms incidence, and their role in risk stratification. We find that heteroplasmy is more common in individuals with clonal hematopoiesis of indeterminate potential, particularly those with higher variant allele fractions, multiple mutations, or spliceosome machinery mutations. Individuals with both markers have a higher risk of myeloid neoplasms than those with either alone. Furthermore, heteroplasmic variants with …

Inferring Tumor Purity Using Multi-Omics Data Based On A Uniform Machine Learning Framework Motp, Qiqi Lu, Zhixian Liu, Xiaosheng Wang

Faculty, Staff and Student Publications

Existing algorithms for assessing tumor purity are limited to a single omics data, such as gene expression, somatic copy number variations, somatic mutations, and DNA methylation. Here we proposed the machine learning Multi-omics Tumor Purity prediction (MoTP) algorithm to estimate tumor purity based on multiple types of omics data. MoTP utilizes the Bayesian Regularized Neural Networks as the prediction algorithm, and Consensus Tumor Purity Estimates as labels. We trained MoTP using multi-omics data (mRNA, microRNA, long non-coding RNA, and DNA methylation) across 21 TCGA solid cancer types. By testing MoTP in TCGA validation sets, TCGA test sets, and eight datasets …

Clc-Kb Pore Mutation Disrupts Glycosylation And Triggers Distal Tubular Remodeling, Yogita Sharma, Robin Lo, Viktor N Tomilin, Kotdaji Ha, Holly Deremo, Aishwarya V Pareek, Wuxing Dong, Xiaohui Liao, Svetlana Lebedeva, Vivek Charu, Neeraja Kambham, Kerim Mutig, Oleh Pochynyuk, Vivek Bhalla

Faculty, Staff and Student Publications

Mutations in the CLCNKB gene (1p36), encoding the basolateral chloride channel ClC-Kb, cause type 3 Bartter syndrome. We identified a family with a mixed Bartter/Gitelman phenotype and early-onset kidney failure and by employing a candidate gene approach, identified what we believe is a novel homozygous mutation (CLCNKB c.499G>T [p.Gly167Cys]) in exon 6 of CLCNKB in the index patient. We then validated these results with Sanger and whole-exome sequencing. Compared with wild-type ClC-Kb, the Gly167Cys mutant conducted less current and exhibited impaired complex N-linked glycosylation in vitro. We demonstrated that loss of Gly-167, rather than gain of a mutant Cys, …

Neuroprotective Effect Of L-Dopa-Induced Interleukin-13 On Striatonigral Degeneration In Cerebral Ischemia, Eunhae Jeon, Myeong-Seong Seo, Enkhmaa Lkhagva-Yondon, Yu-Ree Lim, Seung-Woo Kim, Yu Jeong Kang, Jun Seok Lee, Byoung Dae Lee, Rayul Wi, So-Yoon Won, Young Cheul Chung, Eun S Park, Eunhee Kim, Byung Kwan Jin, Myung-Shin Jeon

Faculty, Staff and Student Publications

Levodopa (L-DOPA) treatment is a clinically effective strategy for improving motor function in patients with ischemic stroke. However, the mechanisms by which modulating the dopamine system relieves the pathology of the ischemic brain remain unclear. Emerging evidence from an experimental mouse model of ischemic stroke, established by middle cerebral artery occlusion (MCAO), suggested that L-DOPA has the potential to modulate the inflammatory and immune response that occurs during a stroke. Here, we aimed to demonstrate the therapeutic effect of L-DOPA in regulating the systemic immune response and improving functional deficits in mice with ischemia. Transient MCAO led to progressive degeneration …

A Proteogenomic Analysis Of Cervical Cancer Reveals Therapeutic And Biological Insights, Jing Yu, Xiuqi Gui, Yunhao Zou, Qian Liu, Zhicheng Yang, Jusheng An, Xuan Guo, Kaihua Wang, Jiaming Guo, Manni Huang, Shuhan Zhou, Jing Zuo, Yimin Chen, Lu Deng, Guangwen Yuan, Ning Li, Yan Song, Jia Jia, Jia Zeng, Yuxi Zhao, Xianming Liu, Xiaoxian Du, Yansheng Liu, Pei Wang, Bing Zhang, Li Ding, Ana I Robles, Henry Rodriguez, Hu Zhou, Zhen Shao, Lingying Wu, Daming Gao

Faculty, Staff and Students Publications

Although the incidence of cervical cancer (CC) has been reduced in high-income countries due to human papillomavirus (HPV) vaccination and screening strategies, it remains a significant public health issue that poses a threat to women's health in low-income countries. Here, we perform a comprehensive proteogenomic profiling of CC tumors obtained from 139 Chinese women. Integrated proteogenomic analysis links genetic aberrations to downstream pathogenesis-related pathways and reveals the landscape of HPV-associated multi-omic changes. EP300 is found to enhance the acetylation of FOSL2-K222, consequently accelerating the malignant proliferation of CC cells. Proteomic stratification identifies three patient subgroups with distinct features in prognosis, …

Identification Of Lrp1+Cd13+ Human Periosteal Stem Cells That Require Lrp1 For Bone Repair, Youngjae Jeong, Lorenzo Deveza, Laura Ortinau, Kevin Lei, John R Dawson, Dongsu Park

Faculty, Staff and Students Publications

Human periosteal skeletal stem cells (P-SSCs) are critical for cortical bone maintenance and repair. However, their in vivo identity, molecular characteristics, and specific markers remain unknown. Here, single-cell sequencing revealed human periosteum contains SSC clusters expressing known SSC markers, podoplanin (PDPN) and PDGFRA. Notably, human P-SSCs, but not bone marrow SSCs, selectively expressed identified markers low density lipoprotein receptor-related protein 1 (LRP1) and CD13. These LRP1+CD13+ human P-SSCs were perivascular cells with high osteochondrogenic but minimal adipogenic potential. Upon transplantation into bone injuries in mice, they preserved self-renewal capability in vivo. Single-cell analysis of mouse periosteum further supported the preferential …

Whole-Genome Analysis Of Plasma Fibrinogen Reveals Population-Differentiated Genetic Regulators With Putative Liver Roles, Jennifer E Huffman, Jayna Nicholas, Julie Hahn, Adam S Heath, Laura M Raffield, Lisa R Yanek, Jennifer A Brody, Florian Thibord, Laura Almasy, Traci M Bartz, Lawrence F Bielak, Russell P Bowler, Germán D Carrasquilla, Daniel I Chasman, Ming-Huei Chen, David B Emmert, Mohsen Ghanbari, Jeffrey Haessler, Jouke-Jan Hottenga, Marcus E Kleber, Ngoc-Quynh Le, Jiwon Lee, Joshua P Lewis, Ruifang Li-Gao, Jian'an Luan, Anni Malmberg, Massimo Mangino, Riccardo E Marioni, Angel Martinez-Perez, Nathan Pankratz, Ozren Polasek, Anne Richmond, Benjamin A T Rodriguez, Jerome I Rotter, Maristella Steri, Pierre Suchon, Stella Trompet, Stefan Weiss, Marjan Zare, Paul Auer, Michael H Cho, Paraskevi Christofidou, Gail Davies, Eco De Geus, Jean-François Deleuze, Graciela E Delgado, Lynette Ekunwe, Nauder Faraday, Martin Gögele, Andreas Greinacher, He Gao, Tom Howard, Peter K Joshi, Tuomas O Kilpeläinen, Jari Lahti, Allan Linneberg, Silvia Naitza, Raymond Noordam, Ferran Paüls-Vergés, Stephen S Rich, Frits R Rosendaal, Igor Rudan, Kathleen A Ryan, Juan Carlos Souto, Frank J A Van Rooij, Heming Wang, Wei Zhao, Lewis C Becker, Andrew Beswick, Michael R Brown, Brian E Cade, Harry Campbell, Kelly Cho, James D Crapo, Joanne E Curran, Moniek P M De Maat, Margaret Doyle, Paul Elliott, James S Floyd, Christian Fuchsberger, Niels Grarup, Xiuqing Guo, Sarah E Harris, Lifang Hou, Ivana Kolcic, Charles Kooperberg, Cristina Menni, Matthias Nauck, Jeffrey R O'Connell, Valeria Orrù, Bruce M Psaty, Katri Räikkönen, Jennifer A Smith, Jose Manuel Soria, David J Stott, Astrid Van Hylckama Vlieg, Hugh Watkins, Gonneke Willemsen, Peter W F Wilson, Yoav Ben-Shlomo, John Blangero, Dorret Boomsma, Simon R Cox, Abbas Dehghan, Johan G Eriksson, Edoardo Fiorillo, Myriam Fornage, Torben Hansen, Caroline Hayward, M Arfan Ikram, J Wouter Jukema, Sharon L R Kardia, Leslie A Lange, Winfried März, Rasika A Mathias, Braxton D Mitchell, Dennis O Mook-Kanamori, Pierre-Emmanuel Morange, Oluf Pedersen, Peter P Pramstaller, Susan Redline, Alexander Reiner, Paul M Ridker, Edwin K Silverman, Tim D Spector, Uwe Völker, Nicholas J Wareham, James F Wilson, Jie Yao, David-Alexandre Trégouët, Andrew D Johnson, Alisa S Wolberg, Paul S De Vries, Maria Sabater-Lleal, Alanna C Morrison, Nicholas L Smith

Faculty, Staff and Student Publications

Genetic studies have identified numerous regions associated with plasma fibrinogen levels in Europeans, yet missing heritability and limited inclusion of non-Europeans necessitates further studies with improved power and sensitivity. Compared with array-based genotyping, whole-genome sequencing (WGS) data provide better coverage of the genome and better representation of non-European variants. To better understand the genetic landscape regulating plasma fibrinogen levels, we meta-analyzed WGS data from the National Heart, Lung, and Blood Institute's Trans-Omics for Precision Medicine (TOPMed) program (n = 32 572), with array-based genotype data from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium (n = 131 …

Initiation Of Hearing Aids Use And Incident Dementia Among Mid-To-Late Life Adults: The Health And Retirement Study 2010-2018, Jingkai Wei, Kun Li, Youngran Kim, Rahul Ghosal, Donglan Zhang, Anwar T Merchant, Casey Crump

Faculty, Staff and Student Publications

BACKGROUND AND OBJECTIVES: Hearing aids may reduce the risk of dementia among individuals with hearing loss. However, no evidence is available from randomized controlled trials (RCTs) on the effectiveness of hearing aids use in reducing incident dementia. Using target trial emulation, we leveraged an existing longitudinal cohort study to estimate the association between hearing aids initiation and risk of dementia.

RESEARCH DESIGN AND METHODS: The Health and Retirement Study was used to emulate target trials among non-institutionalized participants aged ≥50 years with self-reported hearing loss, without dementia at baseline, and without use of hearing aids in the previous 2 years. …

Genetic Risk Classification For Adults With Aml Receiving Less-Intensive Therapies: The 2024 Eln Recommendations, Hartmut Döhner, Courtney D Dinardo, Frederick R Appelbaum, Charles Craddock, Hervé Dombret, Benjamin L Ebert, Pierre Fenaux, Lucy A Godley, Robert P Hasserjian, Richard A Larson, Ross L Levine, Yasushi Miyazaki, Dietger Niederwieser, Gert Ossenkoppele, Christoph Röllig, Jorge Sierra, Eytan M Stein, Martin S Tallman, Hwei-Fang Tien, Jianxiang Wang, Agnieszka Wierzbowska, Andrew H Wei, Bob Löwenberg

Faculty, Staff and Student Publications

The European LeukemiaNet (ELN) genetic risk classifications were developed based on data from younger adults receiving intensive chemotherapy. Emerging analyses from patients receiving less-intensive therapies prompted a proposal for an ELN genetic risk classification specifically for this patient population.

Firearm Access, Carriage And Use In An Ethnically Diverse Sample Of Young Adults In Texas, Usa, Yu Lu, Elizabeth Baumler, Annalyn Saludares Demello, Leila Wood, Hillary Mcguire, Jeff R Temple

Faculty, Staff and Student Publications

Background Despite the high rates of firearm ownership and firearm-related injuries and mortalities in Southern US states, understandings on the factors contributing to these are lacking.

Methods Using wave 10 (2021) data from a longitudinal study, we examined firearm-related experiences among 636 ethnically diverse young adults (mean age=26 years; 62% female) in Texas, USA.

Results Just over half of participants had ready access to firearms, with 22.3% having carried a firearm outside of their home, 4.9% having been threatened with a firearm by a romantic partner and 4.4% by a non-romantic partner. More firearm access and carriage were reported in …

Optimal Management Of Patients With Moderate-To-Severe Inflammatory Bowel Disease, Tugrul Purnak, Atilla Ertan

Faculty, Staff and Student Publications

Inflammatory bowel disease (IBD), encompassing Crohn's disease (CD) and ulcerative colitis (UC), is a chronic and often debilitating condition requiring complex and individualized management. Over the past few decades, advancements in understanding IBD pathophysiology have led to a transformative shift in therapeutic approaches. This article provides a comprehensive overview of the evolution of IBD treatments, from early symptom-focused therapies to modern biologics, small molecule agents, and emerging treatment strategies. We discuss therapeutic goals centered on achieving clinical remission, endoscopic/mucosal healing, and enhancing patient quality of life. Additionally, we explore the rationale for the early and personalized use of biologic therapies …

Genetic Risk Stratification And Outcomes Among Treatment-Naive Patients With Aml Treated With Venetoclax And Azacitidine, Hartmut Döhner, Keith W Pratz, Courtney D Dinardo, Andrew H Wei, Brian A Jonas, Vinod A Pullarkat, Michael J Thirman, Christian Récher, Andre C Schuh, Sunil Babu, Xiaotong Li, Grace Ku, Zihuan Liu, Yan Sun, Jalaja Potluri, Monique Dail, Brenda Chyla, Daniel A Pollyea

Faculty, Staff and Student Publications

The European LeukemiaNet (ELN) acute myeloid leukemia (AML) genetic risk classification systems are based on response to intensive chemotherapy; their ability to discriminate outcomes in older patients treated with venetoclax-azacitidine may be suboptimal. This pooled analysis of the phase 3 VIALE-A trial (NCT02993523) and phase 1b study (NCT02203773) examined prognostic stratification according to the 2017 and 2022 ELN risk classifications and derived new molecular signatures differentiating venetoclax-azacitidine-treated patients based on overall survival (OS). Overall, 279 patients treated with venetoclax-azacitidine and 113 patients treated with placebo-azacitidine were analyzed. The ELN 2017 or 2022 prognostic criteria classified most …

Teen Dating Violence And The Covid-19 Pandemic: Trends From A Longitudinal Study In Texas, Leila Wood, Elizabeth Baumler, Morgan E Pettyjohn, Jeff R Temple

Faculty, Staff and Student Publications

Purpose: Teen dating violence (TDV) is a global public health and safety issue causing health impacts to youth people. This study aimed to examine: (1) the impact of the pandemic on TDV victimisation rates and (2) socioecological factors associated with sustained risk for TDV victimisation during the first year of COVID-19.

Methods: Data are from an ongoing randomised controlled trial of a TDV prevention programme in Texas (n=2768). We conducted annual assessments in 2019-2021. We used regression modelling to assess demographic, individual, peer and family factors associated with TDV risks.

Results: TDV rates declined from 11.9% in 2019 to 5.2% …

Plasmodium Berghei Liver Stage Parasites Exploit Host Gabarap Proteins For Tfeb Activation, Jacqueline Schmuckli-Maurer, Annina F Bindschedler, Rahel Wacker, Oliver M Würgler, Ruth Rehmann, Timothy Lehmberg, Leon O Murphy, Thanh N Nguyen, Michael Lazarou, Jlenia Monfregola, Andrea Ballabio, Volker T Heussler

Duncan NRI Faculty and Staff Publications

Plasmodium, the causative agent of malaria, infects hepatocytes prior to establishing a symptomatic blood stage infection. During this liver stage development, parasites reside in a parasitophorous vacuole (PV), whose membrane acts as the critical interface between the parasite and the host cell. It is well-established that host cell autophagy-related processes significantly impact the development of Plasmodium liver stages. Expression of genes related to autophagy and lysosomal biogenesis is orchestrated by transcription factor EB (TFEB). In this study, we explored the activation of host cell TFEB in Plasmodium berghei-infected cells during the liver stage of the parasite. Our results …

Comparison Of The Bristol Stool Scale And Modified Version For Children: Use By Providers Vs Children, James Orozco, Mariella M Self, Sara Grisales, Bruno P Chumpitazi, Danita I Czyzewski, Meagan S Mcmullen, Rebecca Berger, Clarissa A Gonzalez, Amber L Cunha, Robert J Shulman

Faculty, Staff and Students Publications

Introduction: Accurate report of stool form is essential to diagnosis and assessment of treatment response. The modified Bristol Stool Form Scale for Children (mBSFS-C) classifies stool form into 5 types and is reliable and valid. However, a direct comparison of provider's and children's ratings using the mBSFS-C vs the traditional BSFS that uses 7 stool form types has not been done.

Methods: Pediatric gastroenterology providers and children rated the same 35 stool photographs, reflecting diverse stool forms, using both scales. The order of photograph presentation and scale use were randomized. For each photograph, the most common rating (modal rating) was …

Genotype-Specific Effects Of Elamipretide In Patients With Primary Mitochondrial Myopathy: A Post Hoc Analysis Of The Mmpower-3 Trial, Amel Karaa, Enrico Bertini, Valerio Carelli, Bruce Cohen, Gregory M Ennes, Marni J Falk, Amy Goldstein, Gráinne Gorman, Richard Haas, Michio Hirano, Thomas Klopstock, Mary Kay Koenig, Cornelia Kornblum, Costanza Lamperti, Anna Lehman, Nicola Longo, Maria Judit Molnar, Sumit Parikh, Han Phan, Robert D S Pitceathly, Russekk Saneto, Fernando Scaglia, Serenella Servidei, Mark Tarnopolsky, Antonio Toscano, Johan L K Van Hove, John Vissing, Jerry Vockley, Jeffrey S Finman, Anthony Abbruscato, David A Brown, Alana Sullivan, James A Shiffer, Michelango Mancuso, Mmpower-3 Trial Investigators

Faculty, Staff and Students Publications

BACKGROUND: As previously published, the MMPOWER-3 clinical trial did not demonstrate a significant benefit of elamipretide treatment in a genotypically diverse population of adults with primary mitochondrial myopathy (PMM). However, the prespecified subgroup of subjects with disease-causing nuclear DNA (nDNA) pathogenic variants receiving elamipretide experienced an improvement in the six-minute walk test (6MWT), while the cohort of subjects with mitochondrial DNA (mtDNA) pathogenic variants showed no difference versus placebo. These published findings prompted additional genotype-specific post hoc analyses of the MMPOWER-3 trial. Here, we present these analyses to further investigate the findings and to seek trends and commonalities among those …

Insights Into Human Norovirus Cultivation In Human Intestinal Enteroids, Khalil Ettayebi, Gurpreet Kaur, Ketki Patil, Janam Dave, B Vijayalakshmi Ayyar, Victoria R Tenge, Frederick H Neill, Xi-Lei Zeng, Allison L Speer, Sara C Di Rienzi, Robert A Britton, Sarah E Blutt, Sue E Crawford, Sasirekha Ramani, Robert L Atmar, Mary K Estes

Faculty, Staff and Students Publications

Human noroviruses (HuNoVs) are a significant cause of epidemic and sporadic acute gastroenteritis worldwide. The lack of a reproducible culture system hindered the study of HuNoV replication and pathogenesis for almost a half-century. This barrier was overcome with our successful cultivation of multiple HuNoV strains in human intestinal enteroids (HIEs), which has significantly advanced HuNoV research. We optimized culture media conditions and generated genetically modified HIE cultures to enhance HuNoV replication in HIEs. Building upon these achievements, we now present new insights into this culture system, which involve testing different media, unique HIE lines, and additional virus strains. HuNoV infectivity …

Analyzing Longitudinal Trait Trajectories Using Gwas Identifies Genetic Variants For Kidney Function Decline, Simon Wiegrebe, Mathias Gorski, Janina M Herold, Klaus J Stark, Barbara Thorand, Christian Gieger, Carsten A Böger, Johannes Schödel, Florian Hartig, Han Chen, Thomas W Winkler, Helmut Küchenhoff, Iris M Heid

Faculty, Staff and Student Publications

Understanding the genetics of kidney function decline, or trait change in general, is hampered by scarce longitudinal data for GWAS (longGWAS) and uncertainty about how to analyze such data. We use longitudinal UK Biobank data for creatinine-based estimated glomerular filtration rate from 348,275 individuals to search for genetic variants associated with eGFR-decline. This search was performed both among 595 variants previously associated with eGFR in cross-sectional GWAS and genome-wide. We use seven statistical approaches to analyze the UK Biobank data and simulated data, finding that a linear mixed model is a powerful approach with unbiased effect estimates which is viable …

Phase I Dose Escalation Study Of Io-108, An Anti-Lilrb2 Antibody, In Patients With Advanced Solid Tumors, Matthew H Taylor, Aung Naing, John Powderly, Paul Woodard, Luke Chung, Wen Hong Lin, Hongyu Tian, Nathan Siemers, Hong Xiang, Rong Deng, Kyu Hong, Donna Valencia, Tao Huang, Ying Zhu, X Charlene Liao, Xiao Min Schebye, Manish R Patel

Faculty, Staff and Student Publications

Purpose: In this first-in-human dose escalation study, the safety and efficacy of IO-108, a fully human monoclonal antibody targeting leukocyte immunoglobulin-like receptor B2 (LILRB2), was investigated in patients with advanced solid tumors as monotherapy and in combination with pembrolizumab, an anti-programmed cell death protein 1 (PD-1) antibody.

Methods: The study included patients with histologically or cytologically confirmed advanced and relapsed solid tumors, with measurable disease by Response Evaluation Criteria In Solid Tumors (RECIST) V.1.1. Patients were treated with escalating doses of IO-108 every 3 weeks (Q3W) as monotherapy and in combination with pembrolizumab. Safety and tolerability were the primary objectives. …

Cladribine-Based Therapy For Acute Myeloid Leukemia In Child, Adolescent, And Early Young Adult Patients: The Md Anderson Cancer Center Experience, David Mccall, Shaikha Alqahtani, Moriah Budak, Irtiza Sheikh, Aaron E Fan, Ramya Ramakrishnan, Cesar Nunez, Michael Roth, Miriam B Garcia, Amber Gibson, Naval Daver, Sofia Garces, Nicholas J Short, Ghayas C Issa, Farhad Ravandi, Courtney D Dinardo, Guillermo Montalban Bravo, Guillermo Garcia-Manero, Branko Cuglievan, Tapan Kadia

Faculty, Staff and Student Publications

Background: Cladribine-based combination chemotherapy has demonstrated promising efficacy in patients with relapsed/refractory adult acute myeloid leukemia (AML), prompting its increased utilization in the frontline; in pediatrics, it has been typically reserved for relapsed or refractory cases. While fludarabine has been used more commonly as a purine analog in intensive regimens, cladribine may be an important alternative.

Methods: We performed a retrospective study at MD Anderson Cancer Center from January 2015 to July 2023, which included patients aged 1-21 years with refractory or relapsed AML who received cladribine outside of a transplant conditioning.

Results: A total of 30 patients were included, …

Construction And Evaluation Of A New Rat Reference Genome Assembly, Grcr8, From Long Reads And Long-Range Scaffolding, Kai Li, Melissa L Smith, J Chris Blazier, Kelli J Kochan, Jonathan M D Wood, Kerstin Howe, Anne E Kwitek, Melinda R Dwinell, Hao Chen, Julia L Ciosek, Patrick Masterson, Terence D Murphy, Theodore S Kalbfleisch, Peter A Doris

Faculty, Staff and Student Publications

We report the construction and analysis of a new reference genome assembly for Rattus norvegicus, the laboratory rat, a widely used experimental animal model organism. The assembly has been adopted as the rat reference assembly by the Genome Reference Consortium and is named GRCr8. The assembly has employed 40× Pacific Biosciences (PacBio) HiFi sequencing coverage and scaffolding using optical mapping and Hi-C. We used genomic DNA from a male BN/NHsdMcwi (BN) rat of the same strain and from the same colony as the prior reference assembly, mRatBN7.2. The assembly is at chromosome level with 98.7% of the sequence assigned …

Mitigating Neuroinflammation In Cognitive Areas: Exploring The Impact Of Hmg-Coa Reductase Inhibitor, Carlos Henrique Rocha Catalão, Luis Henrique Angenendt Da Costa, Jonathas Rodrigo Dos Santos, Luciane Carla Alberici, Luiz Luciano Falconi-Sobrinho, Norberto Cysne Coimbra, Diogo Dominguini, Felipe Dal-Pizzol, Tatiana Barichello, Maria José Alves Rocha

Faculty, Staff and Student Publications

Existing literature suggests that infection-specific mechanisms may play a significant role in the onset and progression of dementia, as opposed to the broader phenomenon of systemic inflammation. In addition, 3-hydroxy-3-methylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors have been proposed as a potential therapeutic approach for sepsis, given their anti-inflammatory and antioxidant properties. We investigated the neuroprotective effect of an HMG-CoA reductase inhibitor (simvastatin) by analyzing neurodegenerative markers, mitochondrial respiration, and neuronal tracing in the prefrontal cortex (PFC) and thalamic nucleus reuniens (RE) of sepsis survivor animals. Adult Wistar rats were subjected to sepsis by cecal ligation and puncture or left non-manipulated. …

High-Coverage Nanopore Sequencing Of Samples From The 1000 Genomes Project To Build A Comprehensive Catalog Of Human Genetic Variation, Jonas A Gustafson, Sophia B Gibson, Nikhita Damaraju, Miranda P G Zalusky, Kendra Hoekzema, David Twesigomwe, Lei Yang, Anthony A Snead, Phillip A Richmond, Wouter De Coster, Nathan D Olson, Andrea Guarracino, Qiuhui Li, Angela L Miller, Joy Goffena, Zachary B Anderson, Sophie H R Storz, Sydney A Ward, Maisha Sinha, Claudia Gonzaga-Jauregui, Wayne E Clarke, Anna O Basile, André Corvelo, Catherine Reeves, Adrienne Helland, Rajeeva Lochan Musunuri, Mahler Revsine, Karynne E Patterson, Cate R Paschal, Christina Zakarian, Sara Goodwin, Tanner D Jensen, Esther Robb, 1000 Genomes Ont Sequencing Consortium, University Of Washington Center For Rare Disease Research (Uw-Crdr), Genomics Research To Elucidate The Genetics Of Rare Diseases (Gregor) Consortium, William Richard Mccombie, Fritz J Sedlazeck, Justin M Zook, Stephen B Montgomery, Erik Garrison, Mikhail Kolmogorov, Michael C Schatz, Richard N Mclaughlin, Harriet Dashnow, Michael C Zody, Matt Loose, Miten Jain, Evan E Eichler, Danny E Miller

Faculty, Staff and Students Publications

Fewer than half of individuals with a suspected Mendelian or monogenic condition receive a precise molecular diagnosis after comprehensive clinical genetic testing. Improvements in data quality and costs have heightened interest in using long-read sequencing (LRS) to streamline clinical genomic testing, but the absence of control data sets for variant filtering and prioritization has made tertiary analysis of LRS data challenging. To address this, the 1000 Genomes Project (1KGP) Oxford Nanopore Technologies Sequencing Consortium aims to generate LRS data from at least 800 of the 1KGP samples. Our goal is to use LRS to identify a broader spectrum of variation …

Spatiotemporal Mapping Of Auditory Onsets During Speech Production, Garret Lynn Kurteff, Alyssa M Field, Saman Asghar, Elizabeth C Tyler-Kabara, Dave Clarke, Howard L Weiner, Anne E Anderson, Andrew J Watrous, Robert J Buchanan, Pradeep N Modur, Liberty S Hamilton

Faculty, Staff and Students Publications

The human auditory cortex is organized according to the timing and spectral characteristics of speech sounds during speech perception. During listening, the posterior superior temporal gyrus is organized according to onset responses, which segment acoustic boundaries in speech, and sustained responses, which further process phonological content. When we speak, the auditory system is actively processing the sound of our own voice to detect and correct speech errors in real time. This manifests in neural recordings as suppression of auditory responses during speech production compared with perception, but whether this differentially affects the onset and sustained temporal profiles is not known. …

Leveraging The T2t Assembly To Resolve Rare And Pathogenic Inversions In Reference Genome Gaps, Kristine Bilgrav Saether, Jesper Eisfeldt, Jesse D Bengtsson, Ming Yin Lun, Christopher M Grochowski, Medhat Mahmoud, Hsiao-Tuan Chao, Jill A Rosenfeld, Pengfei Liu, Marlene Ek, Jakob Schuy, Adam Ameur, Hongzheng Dai, Undiagnosed Diseases Network, James Paul Hwang, Fritz J Sedlazeck, Weimin Bi, Ronit Marom, Josephine Wincent, Ann Nordgren, Claudia M B Carvalho, Anna Lindstrand

Faculty, Staff and Students Publications

Chromosomal inversions (INVs) are particularly challenging to detect due to their copy-number neutral state and association with repetitive regions. Inversions represent about 1/20 of all balanced structural chromosome aberrations and can lead to disease by gene disruption or altering regulatory regions of dosage-sensitive genes in cis. Short-read genome sequencing (srGS) can only resolve ∼70% of cytogenetically visible inversions referred to clinical diagnostic laboratories, likely due to breakpoints in repetitive regions. Here, we study 12 inversions by long-read genome sequencing (lrGS) (n = 9) or srGS (n = 3) and resolve nine of them. In four cases, the …

Adjuvant Radiation Therapy In Desmoplastic Melanoma: A Scoping Review, Christina Setareh Sharafi, B Ashleigh Guadagnolo, Kelly C Nelson, Devarati Mitra

Faculty, Staff and Student Publications

Desmoplastic melanoma (DM) is an uncommon subtype of cutaneous melanoma that presents distinct diagnostic and treatment challenges. This review aims to explore the role of adjuvant radiation therapy (RT) in managing DM. To evaluate this question, we reviewed relevant published reports on DM and its treatment and synthesized these findings. It was found that the clinical behavior of DM varies significantly based on its classification as either "pure" DM (pDM, ≥90% desmoplastic features) or mixed DM (mDM, ≤90% desmoplastic features). Patients with pDM have a uniquely high risk of local recurrence but a relatively lower likelihood of nodal disease. Recent …

Delta-Like Ligand 3 (Dll3) Landscape In Pulmonary And Extra-Pulmonary Neuroendocrine Neoplasms, Alejandra G Serrano, Pedro Rocha, Cibelle Freitas Lima, Allison Stewart, Bingnan Zhang, Lixia Diao, Junya Fujimoto, Robert J Cardnell, Wei Lu, Khaja Khan, Beate Sable, Aaron R Ellison, Ignacio I Wistuba, Kyle F Concannon, Daniel M Halperin, Czerniak Bogdan, Kanishka Sircar, Miao Zhang, Kasey Cargill, Qi Wang, Ana Aparicio, Alexander Lazar, Sharia Hernandez, Jeannelyn Estrella, Preetha Ramalingam, Adel El-Naggar, Neda Kalhor, Carl M Gay, Lauren Averett Byers, Luisa M Solis Soto

Faculty, Staff and Student Publications

Delta-like Ligand 3 (DLL3) targeting therapies are promising in small cell lung cancer (SCLC) treatment. However, DLL3 expression in SCLC and other neuroendocrine neoplasms (NEN) is heterogeneous and not well characterized. We describe the landscape of DLL3 at the mRNA and protein levels across SCLC, large cell neuroendocrine carcinoma (LCNEC), and non-small cell lung cancer. Additionally, we explore its expression in extra-pulmonary NEN (EP-NEN) using a standardized DLL3 IHC assay. DLL3 expression is enriched in SCLC, LCNEC along with combined histology lung cancers. Moreover, we find a wide range of DLL3 expression in high-grade EP-NEN. We describe heterogenous DLL3 expression …