Digital Commons Network^™

Alpha Particle-Emitting Radiopharmaceuticals As Cancer Therapy: Biological Basis, Current Status, And Future Outlook For Therapeutics Discovery, Ryan P Coll, Scott J Bright, David K J Martinus, Dimitra K Georgiou, Gabriel O Sawakuchi, H Charles Manning

Faculty, Staff and Student Publications

Critical advances in radionuclide therapy have led to encouraging new options for cancer treatment through the pairing of clinically useful radiation-emitting radionuclides and innovative pharmaceutical discovery. Of the various subatomic particles used in therapeutic radiopharmaceuticals, alpha (α) particles show great promise owing to their relatively large size, delivered energy, finite pathlength, and resulting ionization density. This review discusses the therapeutic benefits of α-emitting radiopharmaceuticals and their pairing with appropriate diagnostics, resulting in innovative "theranostic" platforms. Herein, the current landscape of α particle-emitting radionuclides is described with an emphasis on their use in theranostic development for cancer treatment. Commonly studied radionuclides …

Fair Canonical Correlation Analysis, Zhuoping Zhou, Davoud Ataee Tarzanagh, Bojian Hou, Boning Tong, Jia Xu, Yanbo Feng, Qi Long, Li Shen

Faculty, Staff and Student Publications

This paper investigates fairness and bias in Canonical Correlation Analysis (CCA), a widely used statistical technique for examining the relationship between two sets of variables. We present a framework that alleviates unfairness by minimizing the correlation disparity error associated with protected attributes. Our approach enables CCA to learn global projection matrices from all data points while ensuring that these matrices yield comparable correlation levels to group-specific projection matrices. Experimental evaluation on both synthetic and real-world datasets demonstrates the efficacy of our method in reducing correlation disparity error without compromising CCA accuracy.

Hyperoxidized Prdx3 As A Specific Ferroptosis Marker, Yuelong Yan, Boyi Gan

Faculty, Staff and Student Publications

The lack of a reliable and specific marker for ferroptosis has hindered the advancement of treatments related to this cell death mechanism toward clinical application. A recent study published in Molecular Cell has identified hyperoxidized peroxiredoxin 3 (PRDX3) as a promising marker for ferroptosis, opening up new avenues for monitoring and targeting ferroptosis in disease treatment.

Pathomic Features Reveal Immune And Molecular Evolution From Lung Preneoplasia To Invasive Adenocarcinoma, Pingjun Chen, Frank R Rojas, Xin Hu, Alejandra Serrano, Bo Zhu, Hong Chen, Lingzhi Hong, Rukhmini Bandyoyadhyay, Muhammad Aminu, Neda Kalhor, J Jack Lee, Siba El Hussein, Joseph D Khoury, Harvey I Pass, Andre L Moreira, Vamsidhar Velcheti, Daniel H Sterman, Junya Fukuoka, Kazuhiro Tabata, Dan Su, Lisha Ying, Don L Gibbons, John V Heymach, Ignacio I Wistuba, Junya Fujimoto, Luisa M Solis Soto, Jianjun Zhang, Jia Wu

Faculty, Staff and Student Publications

Recent statistics on lung cancer, including the steady decline of advanced diseases and the dramatically increasing detection of early-stage diseases and indeterminate pulmonary nodules, mark the significance of a comprehensive understanding of early lung carcinogenesis. Lung adenocarcinoma (ADC) is the most common histologic subtype of lung cancer, and atypical adenomatous hyperplasia is the only recognized preneoplasia to ADC, which may progress to adenocarcinoma in situ (AIS) and minimally invasive adenocarcinoma (MIA) and eventually to invasive ADC. Although molecular evolution during early lung carcinogenesis has been explored in recent years, the progress has been significantly hindered, largely due to insufficient materials …

Atm Mutations Associate With Distinct Co-Mutational Patterns And Therapeutic Vulnerabilities In Nsclc, Natalie I Vokes, Ana Galan Cobo, Margarita Fernandez-Chas, David Molkentine, Santiago Treviño, Vitaly Druker, Yu Qian, Sonia Patel, Stephanie Schmidt, Lingzhi Hong, Jeff Lewis, Waree Rinsurongkawong, Vadeerat Rinsurongkawong, J Jack Lee, Marcelo V Negrao, Don L Gibbons, Ara Vaporciyan, Xiuning Le, Jia Wu, Jianjun Zhang, Una Rigney, Sonia Iyer, Emma Dean, John V Heymach

Faculty, Staff and Student Publications

PURPOSE: Ataxia-telangiectasia mutated (ATM) is the most frequently mutated DNA damage repair gene in non-small cell lung cancer (NSCLC). However, the molecular correlates of ATM mutations and their clinical implications have not been fully elucidated.

EXPERIMENTAL DESIGN: Clinicopathologic and genomic data from 26,587 patients with NSCLC from MD Anderson, public databases, and a de-identified nationwide (US-based) NSCLC clinicogenomic database (CGDB) were used to assess the co-mutation landscape, protein expression, and mutational processes in ATM-mutant tumors. We used the CGDB to evaluate ATM-associated outcomes in patients treated with immune checkpoint inhibitors (ICI) with or without chemotherapy, and assessed the effect of …

Biomechanical Evaluation Of Mitral Valve Repair: Virtual Chordal Transposition To Restore Anterior Leaflet Prolapse, Soohwan Jeong, Seong-Min Kim, Woojae Hong, Minsung Ko, David D Mcpherson, Hyunggun Kim

Faculty, Staff and Student Publications

Background: Surgical management of an anterior leaflet prolapse remains comparatively challenging and has led to the lack of any firmly established standard repair techniques, as seen in cases of posterior leaflet prolapse. Chordal transposition repair is widely acknowledged as a remarkably durable technique that utilizes the patient's native chordae. This study aims to evaluate and predict the biomechanical and functional characteristics of a normal mitral valve (MV) model and a pathological MV model featuring anterior ruptured mitral chordae tendineae (RMCT), and to assess the effectiveness of the chordal transposition repair in the pathological MV model.

Methods: There are four stages …

Relapse Recovery In Relapsing-Remitting Multiple Sclerosis: An Analysis Of The Combirx Dataset, Marcus W Koch, Ester Moral, Luis Brieva, Jop Mostert, Eva Mm Strijbis, Jacynthe Comtois, Pavle Repovic, James D Bowen, Jerry S Wolinsky, Fred D Lublin, Gary Cutter

Faculty, Staff and Student Publications

Background: Clinical relapses are the defining feature of relapsing forms of multiple sclerosis (MS), but relatively little is known about the time course of relapse recovery.

Objective: The aim of this study was to investigate the time course of and patient factors associated with the speed and success of relapse recovery in people with relapsing-remitting MS (RRMS).

Methods: Using data from CombiRx, a large RRMS trial (clinicaltrials.gov identifier NCT00211887), we measured the time to recovery from the first on-trial relapse. We used Kaplan-Meier survival analyses and Cox regression models to investigate the association of patient factors with the time …

Oral Glucose Tolerance Test In Pregnancy And Subsequent Maternal Hypertension, Maged M Costantine, Madeline Murguia Rice, Mark B Landon, Michael W Varner, Brian M Casey, Uma M Reddy, Ronald J Wapner, Dwight J Rouse, Alan T N Tita, John M Thorp, Edward K Chien, Alan M Peaceman, Sean C Blackwell

Faculty, Staff and Student Publications

Objective: The aim of the study is to evaluate whether values and the shape of the glucose curve during the oral glucose tolerance test (OGTT) in pregnancy identify women at risk of developing hypertension (HTN) later in life.

Study design: This category includes the secondary analysis of a follow-up from a mild gestational diabetes mellitus (GDM) study that included a treatment trial for mild GDM (n = 458) and an observational cohort of participants with abnormal 1-hour glucose loading test only (normal OGTT, n = 430). Participants were assessed at a median of 7 (IQR 6-8) years after their …

Systematic Review And Meta-Analysis Of Immune Checkpoint Inhibitors As Single Agent Or In Combination With Chemotherapy In Early-Stage Non-Small Cell Lung Cancer: Impact Of Clinicopathological Factors And Indirect Comparison Between Treatment Strategies, Antonio Nuccio, Giuseppe Viscardi, Fabio Salomone, Alberto Servetto, Francesco Maria Venanzi, Silvia Teresa Riva, Sara Oresti, Francesca Rita Ogliari, Mariagrazia Viganò, Alessandra Bulotta, Robert Cameron, Alessandra Esposito, Jacobi Hines, Roberto Bianco, Michele Reni, Tina Cascone, Marina Chiara Garassino, Valter Torri, Giulia Veronesi, Michela Cinquini, Roberto Ferrara

Faculty, Staff and Student Publications

Background: In non-small cell lung cancer (NSCLC), the immune checkpoint inhibitors (ICI) revolution is rapidly moving from metastatic to early-stage, however, the impact of clinicopathological variables and optimal treatment sequencing remain unclear.

Methods: Randomized controlled trials (RCTs) in patients with early-stage NSCLC treated with ICI as single agent or in combination with platinum-based chemotherapy (PCT) were included. Primary outcomes were pathological complete response (pCR), event free survival (EFS) (neoadjuvant/perioperative), and disease-free survival (DFS) (adjuvant). Secondary outcomes were major pathological response (MPR), overall survival (OS), toxicity, surgical outcomes (neoadjuvant/perioperative); OS and toxicity (adjuvant). An additional secondary endpoint was to compare EFS …

Competing Engagement Of Β-Arrestin Isoforms Balances Igf1r/P53 Signaling And Controls Melanoma Cell Chemotherapeutic Responsiveness, Sonia Cismas, Sylvya Pasca, Caitrin Crudden, Iara Trocoli Drakensjo, Naida Suleymanova, Simin Zhang, Benjamin Gebhard, Dawei Song, Shiyong Neo, Takashi Shibano, Terry J Smith, George A Calin, Ada Girnita, Leonard Girnita

Faculty, Staff and Student Publications

Constraints on the p53 tumor suppressor pathway have long been associated with the progression, therapeutic resistance, and poor prognosis of melanoma, the most aggressive form of skin cancer. Likewise, the insulin-like growth factor type 1 receptor (IGF1R) is recognized as an essential coordinator of transformation, proliferation, survival, and migration of melanoma cells. Given that β-arrestin (β-arr) system critically governs the anti/pro-tumorigenic p53/IGF1R signaling pathways through their common E3 ubiquitin-protein ligase MDM2, we explore whether unbalancing this system downstream of IGF1R can enhance the response of melanoma cells to chemotherapy. Altering β-arr expression demonstrated that both β-arr1-silencing and β-arr2-overexpression (-β-arr1/+β-arr2) facilitated …

Genomic Profiles And Clinical Outcomes Of Penile Squamous Cell Carcinoma With Elevated Tumor Mutational Burden, Andrea Necchi, Philippe E Spiess, Tiago Costa De Padua, Roger Li, Petros Grivas, Richard S P Huang, Douglas I Lin, Natalie Danziger, Jeffrey S Ross, Joseph M Jacob, Rebecca A Sager, Alina Basnet, Gerald Li, Ryon P Graf, Dean C Pavlick, Gennady Bratslavsky

Faculty, Staff and Student Publications

IMPORTANCE: Tumor mutational burden (TMB) is a putative biomarker of efficacy for immune checkpoint inhibitor (ICI) therapies of solid tumors, but not specifically for penile squamous cell carcinoma (PSCC).

OBJECTIVE: To characterize biomarker features and ICI therapy outcomes associated with high TMB in PSCC in the routine clinical practice setting.

DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, 397 PSCC cases were analyzed to identify genomic alterations in more than 300 cancer-associated genes and genomic signatures, including TMB, using a hybrid capture-based comprehensive genomic profiling assay. Tumor mutational burden was categorized as low ([mut/Mb]), high (10-19 mut/Mb), or very high …

The Application Of Simultaneous Mainstem Bronchus Dilation With Pulmonary Artery Stenting In The Context Of Hypoplastic Left Heart Syndrome, Sylwia Hasterok, Thomas G Scott, Devin G Roller, Adam Spencer, Arun B Dutta, Kizhakke M Sathyan, Daniel E Frigo, Michael J Guertin, Daniel Gioeli

Faculty, Staff and Student Publications

The clinical success of combined androgen deprivation therapy (ADT) and radiotherapy (RT) in prostate cancer created interest in understanding the mechanistic links between androgen receptor (AR) signaling and the DNA damage response (DDR). Convergent data have led to a model where AR both regulates, and is regulated by, the DDR. Integral to this model is that the AR regulates the transcription of DDR genes both at a steady state and in response to ionizing radiation (IR). In this study, we sought to determine which immediate transcriptional changes are induced by IR in an AR-dependent manner. Using PRO-seq to quantify changes …

Systematic Analysis Of Proximal Midgut- And Anorectal-Originating Contractions In Larval Zebrafish Using Event Feature Detection And Supervised Machine Learning Algorithms, Ryan M Cassidy, Erika M Flores, Anh K Trinh Nguyen, Sai S Cheruvu, Rosa A Uribe, Anne Marie Krachler, Max A Odem

Faculty, Staff and Student Publications

Background: Zebrafish larvae are translucent, allowing in vivo analysis of gut development and physiology, including gut motility. While recent progress has been made in measuring gut motility in larvae, challenges remain which can influence results, such as how data are interpreted, opportunities for technical user error, and inconsistencies in methods.

Methods: To overcome these challenges, we noninvasively introduced Nile Red fluorescent dye to fill the intraluminal gut space in zebrafish larvae and collected serial confocal microscopic images of gut fluorescence. We automated the detection of fluorescent-contrasted contraction events against the median-subtracted signal and compared it to manually annotated gut contraction …

Genome-Wide Significant Risk Loci For Mood Disorders In The Old Order Amish Founder Population, Elizabeth M Humphries, Kwangmi Ahn, Rachel L Kember, Fabiana L Lopes, Evelina Mocci, Juan M Peralta, John Blangero, David C Glahn, Fernando S Goes, Peter P Zandi, Peter Kochunov, Cristopher Van Hout, Alan R Shuldiner, Toni I Pollin, Braxton D Mitchell, Maja Bucan, L Elliot Hong, Francis J Mcmahon, Seth A Ament

Faculty, Staff and Student Publications

Genome-wide association studies (GWAS) of mood disorders in large case-control cohorts have identified numerous risk loci, yet pathophysiological mechanisms remain elusive, primarily due to the very small effects of common variants. We sought to discover risk variants with larger effects by conducting a genome-wide association study of mood disorders in a founder population, the Old Order Amish (OOA, n = 1,672). Our analysis revealed four genome-wide significant risk loci, all of which were associated with >2-fold relative risk. Quantitative behavioral and neurocognitive assessments (n = 314) revealed effects of risk variants on sub-clinical depressive symptoms and information processing speed. Network …

Acute Myeloid Leukemia With Mutated Tp53: Is This Newly Proposed Entity Oversimplifying A Complex Group Of Neoplasms?, Hong Fang, L Jeffery Medeiros, Wei Wang

Faculty, Staff and Student Publications

No abstract provided.

Achondroplasia Natural History Study (Clarity): 60-Year Experience With Hydrocephalus In Achondroplasia From Four Skeletal Dysplasia Centers, Jeffrey Campbell, Janet M Legare, Joseph Piatt, Ethan Gough, Richard M Pauli, S Shahrukh Hashmi, David F Rodriguez-Buritica, Peggy Modaff, Mary Ellen Little, Maria Elena Serna, Cory J Smid, Lorena Dujmusic, Jacqueline T Hecht, Julie E Hoover-Fong, Michael B Bober

Faculty, Staff and Student Publications

Objective: The objective of this study was to describe the incidence and management of hydrocephalus in patients with achondroplasia over a 60-year period at four skeletal dysplasia centers.

Methods: The Achondroplasia Natural History Study (CLARITY) is a registry for clinical data from achondroplasia patients receiving treatment at four skeletal dysplasia centers in the US from 1957 to 2017. Data were entered and stored in a REDCap database and included surgeries with indications and complications, medical diagnoses, and radiographic information.

Results: A total of 1374 patients with achondroplasia were included in this study. Of these, 123 (9%) patients underwent treatment of …

Cbx4 Promotes Antitumor Immunity By Suppressing Pdcd1 Expression In T Cells, Liwei Ren, Ziyin Li, Yu Zhou, Jun Zhang, Ziheng Zhao, Zhaofei Wu, Ye Zhao, Yurong Ju, Xuewen Pang, Xiuyuan Sun, Wei Wang, Yu Zhang

Faculty, Staff and Student Publications

E3 SUMO-protein ligase CBX4 (CBX4), a key component of polycomb-repressive complexes 1 (PRC1), has been reported to regulate a variety of genes implicated in tumor growth, metastasis, and angiogenesis. However, its role in T-cell-mediated antitumor immunity remains elusive. To shed light on this issue, we generated mice with T-cell-specific deletion of Cbx4. Tumor growth was increased in the knockout mice. Additionally, their tumor-infiltrating lymphocytes exhibited impaired tumor necrosis factor-alpha (TNF-α) and interferon-gamma (IFN-γ) production, with an elevated programmed cell death protein 1 (PD-1) level. In fact, dysregulated Pdcd1 expression was observed in all major subsets of peripheral T cells from …

Development And Validation Of Age-Specific Risk Prediction Models For Primary Ovarian Insufficiency In Long-Term Survivors Of Childhood Cancer: A Report From The Childhood Cancer Survivor Study And St Jude Lifetime Cohort, Cindy Im, Zhe Lu, Sogol Mostoufi-Moab, Angela Delaney, Lin Yu, Jessica L Baedke, Yutong Han, Yadav Sapkota, Yutaka Yasui, Eric J Chow, Rebecca M Howell, Smita Bhatia, Melissa M Hudson, Kirsten K Ness, Gregory T Armstrong, Paul C Nathan, Yan Yuan

Faculty, Staff and Student Publications

BACKGROUND: Female survivors of childhood cancer are at risk for primary ovarian insufficiency (POI), defined as the cessation of gonadal function before the age of 40 years. We aimed to develop and validate models to predict age-specific POI risk among long-term survivors of childhood cancer.

METHODS: To develop models to predict age-specific POI risk for the ages of 21-40 years, we used data from the Childhood Cancer Survivor Study (CCSS). Female survivors aged 18 years or older at their latest follow-up, with self-reported menstrual history information and free of subsequent malignant neoplasms within 5 years of diagnosis, were included. We …

Enhanced Cd19 Activity In B Cells Contributes To Immunodeficiency In Mice Deficient In The Icf Syndrome Gene Zbtb24, Zhengzhou Ying, Swanand Hardikar, Joshua B Plummer, Tewfik Hamidi, Bin Liu, Yueping Chen, Jianjun Shen, Yunxiang Mu, Kevin M Mcbride, Taiping Chen

Faculty, Staff and Student Publications

Immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a rare autosomal recessive disorder characterized by DNA hypomethylation and antibody deficiency. It is caused by mutations in DNMT3B, ZBTB24, CDCA7, or HELLS. While progress has been made in elucidating the roles of these genes in regulating DNA methylation, little is known about the pathogenesis of the life-threatening hypogammaglobulinemia phenotype. Here, we show that mice deficient in Zbtb24 in the hematopoietic lineage recapitulate the major clinical features of patients with ICF syndrome. Specifically, Vav-Cre-mediated ablation of Zbtb24 does not affect lymphocyte development but results in reduced plasma cells and low levels …

“Be Sustainable”: Eosc-Life Recommendations For Implementation Of Fair Principles In Life Science Data Handling, Romain David, Arina Rybina, Jean-Marie Burel, Jean-Karim Heriche, Pauline Audergon, Jan-Willem Boiten, Frederik Coppens, Sara Crockett, Katrina Exter, Sven Fahrner, Maddalena Fratelli, Carole Goble, Philipp Gormanns, Tobias Grantner, Björn Grüning, Kim Tamara Gurwitz, John M Hancock, Henriette Harmse, Petr Holub, Nick Juty, Geoffrey Karnbach, Emma Karoune, Antje Keppler, Jessica Klemeier, Carla Lancelotti, Jean-Luc Legras, Allyson L Lister, Dario Livio Longo, Rebecca Ludwig, Bénédicte Madon, Marzia Massimi, Vera Matser, Rafaele Matteoni, Michaela Th Mayrhofer, Christian Ohmann, Maria Panagiotopoulou, Helen Parkinson, Isabelle Perseil, Claudia Pfander, Roland Pieruschka, Michael Raess, Andreas Rauber, Audrey S Richard, Paolo Romano, Antonio Rosato, Alex Sánchez-Pla, Susanna-Assunta Sansone, Ugis Sarkans, Beatriz Serrano-Solano, Jing Tang, Ziaurrehman Tanoli, Jonathan Tedds, Harald Wagener, Martin Weise, Hans V Westerhoff, Rudolf Wittner, Jonathan Ewbank, Niklas Blomberg, Philip Gribbon

Faculty, Staff and Student Publications

The main goals and challenges for the life science communities in the Open Science framework are to increase reuse and sustainability of data resources, software tools, and workflows, especially in large-scale data-driven research and computational analyses. Here, we present key findings, procedures, effective measures and recommendations for generating and establishing sustainable life science resources based on the collaborative, cross-disciplinary work done within the EOSC-Life (European Open Science Cloud for Life Sciences) consortium. Bringing together 13 European life science research infrastructures, it has laid the foundation for an open, digital space to support biological and medical research. Using lessons learned from …

Physiological And Molecular Bases Of The Boron Deficiency Response In Tomatoes, Junjun Li, Huihui Fan, Qianqian Song, Lili Jing, Hao Yu, Ruishan Li, Ping Zhang, Fei Liu, Weimin Li, Liangliang Sun, Jin Xu

Faculty, Staff and Student Publications

Boron is an essential microelement for plant growth. Tomato is one of the most cultivated fruits and vegetables in the world, and boron deficiency severely inhibits its yield and quality. However, the mechanism of tomato in response to boron deficiency remains largely unclear. Here, we investigated the physiological and molecular bases of the boron deficiency response in hydroponically grown tomato seedlings. Boron deficiency repressed the expression of genes associated with nitrogen metabolism, while it induced the expression of genes related to the pentose phosphate pathway, thereby altering carbon flow to provide energy for plants to cope with stress. Boron deficiency …

Sam: Self-Adapting Mixture Prior To Dynamically Borrow Information From Historical Data In Clinical Trials, Peng Yang, Yuansong Zhao, Lei Nie, Jonathon Vallejo, Ying Yuan

Faculty, Staff and Student Publications

Mixture priors provide an intuitive way to incorporate historical data while accounting for potential prior-data conflict by combining an informative prior with a noninformative prior. However, prespecifying the mixing weight for each component remains a crucial challenge. Ideally, the mixing weight should reflect the degree of prior-data conflict, which is often unknown beforehand, posing a significant obstacle to the application and acceptance of mixture priors. To address this challenge, we introduce self-adapting mixture (SAM) priors that determine the mixing weight using likelihood ratio test statistics or Bayes factors. SAM priors are data-driven and self-adapting, favoring the informative (noninformative) prior component …

Sleep Duration, Sleep Quality, And Weapon Carrying In A Sample Of Adolescents From Texas, Arthur Stefanski, Eduardo Pérez-Palma, Tobias Brünger, Ludovica Montanucci, Cornelius Gati, Chiara Klöckner, Katrine M Johannesen, Kimberly Goodspeed, Marie Macnee, Alexander T Deng, Ángel Aledo-Serrano, Artem Borovikov, Maina Kava, Arjan M Bouman, M J Hajianpour, Deb K Pal, Marc Engelen, Eveline E O Hagebeuk, Marwan Shinawi, Alexis R Heidlebaugh, Kathryn Oetjens, Trevor L Hoffman, Pasquale Striano, Amanda S Freed, Line Futtrup, Thomas Balslev, Anna Abulí, Leslie Danvoye, Damien Lederer, Tugce Balci, Maryam Nabavi Nouri, Elizabeth Butler, Sarah Drewes, Kalene Van Engelen, Katherine B Howell, Jean Khoury, Patrick May, Marena Trinidad, Steven Froelich, Johannes R Lemke, Jacob Tiller, Amber N Freed, Jing-Qiong Kang, Arthur Wuster, Rikke S Møller, Dennis Lal

Faculty, Staff and Student Publications

Genetic variants in the SLC6A1 gene can cause a broad phenotypic disease spectrum by altering the protein function. Thus, systematically curated clinically relevant genotype-phenotype associations are needed to understand the disease mechanism and improve therapeutic decision-making.

We aggregated genetic and clinical data from 172 individuals with likely pathogenic/pathogenic (lp/p) SLC6A1 variants and functional data for 184 variants (14.1% lp/p). Clinical and functional data were available for a subset of 126 individuals. We explored the potential associations of variant positions on the GAT1 3D structure with variant pathogenicity, altered molecular function and phenotype severity using bioinformatic approaches.

The GAT1 transmembrane domains …

Behavioral Or Neuropsychiatric Symptoms Of Alzheimer’S Disease: From Psychopathology To Pharmacological Management, Antonio Lucio Teixeira, Natalia Pessoa Rocha, Jennifer Gatchel

Faculty, Staff and Student Publications

Neuropsychiatric or behavioral symptoms of dementia encompass a series of disorders, such as anxiety, depression, apathy, psychosis, and agitation, all commonly present in individuals living with dementia. While they are not required for the diagnosis of Alzheimer's disease (AD), they are ubiquitously present in all stages of the disease, contributing to negative clinical outcomes, including cognitive decline, functional disability, and caregiver burden. Neuropsychiatric symptoms have been conceptualized not only as risk factors but as clinical markers of decline along the AD spectrum. The concept of "mild behavioral impairment", the behavioral correlate of mild cognitive impairment, has been proposed within this …

Editorial: Innovations, Advances, And Challenges In Precision Radiation Oncology Physics, Fada Guan, Lawrence Bronk, Jinbo Yue, Radhe Mohan, Zhe Chen

Faculty, Staff and Student Publications

No abstract provided.

Improving Radiotherapy In Immunosuppressive Microenvironments By Targeting Complement Receptor C5ar1, Callum Beach, David Maclean, Dominika Majorova, Stavros Melemenidis, Dhanya K Nambiar, Ryan K Kim, Gabriel N Valbuena, Silvia Guglietta, Carsten Krieg, Mahnaz Darvish-Damavandi, Tatsuya Suwa, Alistair Easton, Lily Vs Hillson, Ashley K Mcculloch, Ross K Mcmahon, Kathryn Pennel, Joanne Edwards, Sean M O'Cathail, Campbell S Roxburgh, Enric Domingo, Eui Jung Moon, Dadi Jiang, Yanyan Jiang, Qingyang Zhang, Albert C Koong, Trent M Woodruff, Edward E Graves, Tim Maughan, Simon Ja Buczacki, Manuel Stucki, Quynh-Thu Le, Simon J Leedham, Amato J Giaccia, Monica M Olcina

Faculty, Staff and Student Publications

An immunosuppressive microenvironment causes poor tumor T cell infiltration and is associated with reduced patient overall survival in colorectal cancer. How to improve treatment responses in these tumors is still a challenge. Using an integrated screening approach to identify cancer-specific vulnerabilities, we identified complement receptor C5aR1 as a druggable target, which when inhibited improved radiotherapy, even in tumors displaying immunosuppressive features and poor CD8+ T cell infiltration. While C5aR1 is well-known for its role in the immune compartment, we found that C5aR1 is also robustly expressed on malignant epithelial cells, highlighting potential tumor cell-specific functions. C5aR1 targeting resulted in increased …

Effect Of Epithelial-Specific Myd88 Signaling Pathway On Airway Inflammatory Response To Organic Dust Exposure, Amber N Johnson, John Dickinson, Amy Nelson, Rohit Gaurav, Katrina Kudrna, Scott E Evans, Katherine Janike, Todd A Wyatt, Jill A Poole

Faculty, Staff and Student Publications

The Toll-like receptor (TLR) adaptor protein MyD88 is integral to airway inflammatory response to microbial-enriched organic dust extract (ODE) exposures. ODE-induced airway neutrophil influx and release of pro-inflammatory cytokines was essentially abrogated in global MyD88-deficient mice, yet these mice demonstrate an increase in airway epithelial cell mucin expression. To further elucidate the role of MyD88-dependent responses specific to lung airway epithelial cells in response to ODE in vivo, the surfactant protein C protein (SPC) Cre+ embryologic expressing airway epithelial cells floxed for MyD88 to disrupt MyD88 signaling were utilized. The inducible club cell secretory protein (CCSP) Cre+, MyD88 floxed, …

Inhibition Of The Proline Metabolism Rate-Limiting Enzyme P5cs Allows Proliferation Of Glutamine-Restricted Cancer Cells, Samantha J Linder, Tiziano Bernasocchi, Bárbara Martínez-Pastor, Kelly D Sullivan, Matthew D Galbraith, Caroline A Lewis, Christina M Ferrer, Ruben Boon, Giorgia G Silveira, Hyo Min Cho, Charles Vidoudez, Stuti Shroff, Joao P Oliveira-Costa, Kenneth N Ross, Rami Massri, Yusuke Matoba, Eugene Kim, Bo R Rueda, Shannon L Stott, Eyal Gottlieb, Joaquin M Espinosa, Raul Mostoslavsky

Faculty, Staff and Student Publications

Glutamine is a critical metabolite for rapidly proliferating cells as it is used for the synthesis of key metabolites necessary for cell growth and proliferation. Glutamine metabolism has been proposed as a therapeutic target in cancer and several chemical inhibitors are in development or in clinical trials. How cells subsist when glutamine is limiting is poorly understood. Here, using an unbiased screen, we identify ALDH18A1, which encodes P5CS, the rate-limiting enzyme in the proline biosynthetic pathway, as a gene that cells can downregulate in response to glutamine starvation. Notably, P5CS downregulation promotes de novo glutamine synthesis, highlighting a previously unrecognized …

Set-Pp2a Complex As A New Therapeutic Target In Kmt2a (Mll) Rearranged Aml, Antonella Di Mambro, Yoana Arroyo-Berdugo, Tiziana Fioretti, Michael Randles, Luca Cozzuto, Vinothini Rajeeve, Armando Cevenini, Michael J Austin, Gabriella Esposito, Julia Ponomarenko, Claire M Lucas, Pedro Cutillas, John Gribben, Owen Williams, Yolanda Calle, Bela Patel, Maria Teresa Esposito

Faculty, Staff and Student Publications

KMT2A-rearranged (KMT2A-R) is an aggressive and chemo-refractory acute leukemia which mostly affects children. Transcriptomics-based characterization and chemical interrogation identified kinases as key drivers of survival and drug resistance in KMT2A-R leukemia. In contrast, the contribution and regulation of phosphatases is unknown. In this study we uncover the essential role and underlying mechanisms of SET, the endogenous inhibitor of Ser/Thr phosphatase PP2A, in KMT2A-R-leukemia. Investigation of SET expression in acute myeloid leukemia (AML) samples demonstrated that SET is overexpressed, and elevated expression of SET is correlated with poor prognosis and with the expression of MEIS and HOXA genes in AML patients. …

Clinico-Genomic Profiling Of Conventional And Dedifferentiated Chondrosarcomas Reveals Tp53 Mutation To Be Associated With Worse Outcomes, Ryan A Denu, Richard K Yang, Alexander J Lazar, Shalin S Patel, Valerae O Lewis, Jason Roszik, J Andrew Livingston, Wei-Lien Wang, Kenna R Shaw, Ravin Ratan, Maria A Zarzour, Justin Bird, Shaan Raza, Kadir C Akdemir, Jordi Rodon Ahnert, Vivek Subbiah, Shreyaskumar Patel, Anthony P Conley

Faculty, Staff and Student Publications

PURPOSE: Chondrosarcomas are the most common primary bone tumor in adults. Isocitrate dehydrogenase 1 (IDH1) and IDH2 mutations are prevalent. We aimed to assess the clinico-genomic properties of IDH mutant versus IDH wild-type (WT) chondrosarcomas as well as alterations in other genes.

EXPERIMENTAL DESIGN: We included 93 patients with conventional and dedifferentiated chondrosarcoma for which there were available clinical next-generation sequencing data. Clinical and genomic data were extracted and compared between IDH mutant and IDH WT chondrosarcomas and between TP53 mutant and TP53 WT chondrosarcomas.

RESULTS: IDH1 and IDH2 mutations are prevalent in chondrosarcoma (50.5%), more common in chondrosarcomas arising …