Biomedical Informatics Commons^™

Meta-Analysis Of The Vmp-Like Sequences Of Lyme Disease Borrelia: Evidence For The Evolution Of An Elaborate Antigenic Variation System, Steven J Norris, Kalvis Brangulis

Faculty, Staff and Student Publications

VMP-like sequence (vls) antigenic variation systems are present in every Lyme disease Borrelia strain with complete genome sequences. The linear plasmid-encoded vls system consists of a single expression site (vlsE) and contiguous array(s) of silent cassettes that have ~90% identity with the central cassette region of the cognate vlsE gene; antigenic variation occurs through random, segmental, and unidirectional recombination of vls silent cassette sequences into the vlsE expression site. Automated annotation programs do not accurately recognize vls silent cassette sequences, so these regions are not correctly annotated in most genomic sequences. In this study, the vls …

Best Practice Recommendations For The Management Of Anxiety During The Pegvaliase Journey, Kendra J Bjoraker, Caroline Eggerding, Elisheva Ellenberg, Suzanne Hollander, Brittany M Holmes, Kristin Lindstrom, Markey Mcnutt, Suzanne Miller, Hope Northrup, Meaghan Rogers, Sarah Rose, Mia Scott, Soo Shim, Bridget Wardley, Leah Wessenberg, Deborah A Bilder

Faculty, Staff and Student Publications

Background: Pegvaliase, an enzyme substitution therapy, is a treatment option for phenylketonuria (PKU). Due to the neuropathophysiology and disease burden of PKU, individuals can experience baseline anxiety unrelated to pegvaliase therapy. In addition, there are aspects of pegvaliase therapy that may be anxiety-inducing for those considering or receiving treatment. The aim of this manuscript is to present best practice recommendations for the identification and management of anxiety symptoms that can occur along the pegvaliase journey.

Methods: A modified Delphi approach was used to seek consensus among a multidisciplinary panel of experts. To this end, an in-person meeting was held that …

Multicenter Randomized Controlled Trial Of Exercise In Aortic Dissection Survivors: Rationale, Design, And Initial Hemodynamic Data, Yasmin A Toy, Kayla N House, Leslie M Boyer, Jennifer L Mcnamara, Marion A Hofmann-Bowman, Kim A Eagle, Michelle S Lim, Alan C Braverman, Siddharth K Prakash

Faculty, Staff and Student Publications

Aims: There are currently no evidence-based guidelines for exercise after thoracic aortic dissection (TAD), leading to highly variable recommendations that frequently lead patients to restrict their physical activities. This multicenter randomized controlled trial was intended to evaluate the safety and efficacy of a moderate intensity guided exercise program for TAD survivors.

Methods: Participants were eligible if they had a Type A or Type B dissection at least 90 days before enrollment and could attend two in-person study visits. The guided exercise circuit consisted of six aerobic, isotonic, or isometric exercises that participants continued at home with virtual follow-up sessions. The …

Metformin In Conjunction With Stereotactic Radiotherapy For Early-Stage Non-Small Cell Lung Cancer: Long-Term Results Of A Prospective Phase Ii Clinical Trial, Molly K Tate, Mike Hernandez, Joe Y Chang, Steven H Lin, Zhongxing Liao, Suja M Koshy, Heath D Skinner, Stephen G Chun

Faculty, Staff and Student Publications

Background/aim: Non-small cell lung cancer (NSCLC) is increasingly detected in early stages and there is interest in improving outcomes with stereotactic body radiotherapy (SBRT). As metformin affects NSCLC signaling pathways, it might alter the metabolism of NSCLC treated with SBRT. This study investigated the long-term outcomes of a phase II clinical trial evaluating metformin in conjunction with SBRT for early-stage NSCLC.

Patients and methods: The trial evaluated patients with American Joint Commission on Cancer (AJCC) 7th edition Stage I-II, cT1-T2N0M0 NSCLC who were randomized 6:1 to receive metformin versus placebo in conjunction with SBRT. The outcomes analyzed included local failure …

Analysis Of B7-H4 Expression Across Salivary Gland Carcinomas Reveals Adenoid Cystic Carcinoma-Specific Prognostic Relevance, Juliana Mota Siqueira, Yoshitsugu Mitani, Camilla Oliveira Hoff, Flavia Bonini, Luana Guimaraes De Sousa, Mario L Marques-Piubelli, Anurag Purushothaman, Mutsumi Mitani, Hui Dai, Shiaw-Yih Lin, Michael T Spiotto, Ehab Y Hanna, Daniel J Mcgrail, Adel K El-Naggar, Renata Ferrarotto

Faculty, Staff and Student Publications

B7-H4 (VTCN1), a member of the B7 family, is overexpressed in several types of cancer. Here we investigated the pattern of expression of B7-H4 in salivary gland carcinomas (SGC) and assessed its potential as a prognostic marker and therapeutic target. Immunohistochemistry (IHC) analyses were performed in a cohort of 340 patient tumors, composed of 124 adenoid cystic carcinomas (ACC), 107 salivary duct carcinomas (SDC), 64 acinic cell carcinomas, 36 mucoepidermoid carcinomas (MEC), 9 secretory carcinomas (SC), as well as 20 normal salivary glands (controls). B7-H4 expression was scored and categorized into negative (< 5% expression of any intensity), low (5%-70% expression of any intensity or >70% with weak intensity), or high ( …

Predicting Suicidality In Late-Life Depression By 3d Convolutional Neural Network And Cross-Sample Entropy Analysis Of Resting-State Fmri, Chemin Lin, Chih-Mao Huang, Wei Chang, You-Xun Chang, Ho-Ling Liu, Shu-Hang Ng, Huang-Li Lin, Tatia Mei-Chun Lee, Shwu-Hua Lee, Shun-Chi Wu

Faculty, Staff and Student Publications

Background: Predicting suicide is a pressing issue among older adults; however, predicting its risk is difficult. Capitalizing on the recent development of machine learning, considerable progress has been made in predicting complex behavior such as suicide. As depression remained the strongest risk for suicide, we aimed to apply deep learning algorithms to identify suicidality in a group with late-life depression (LLD).

Methods: We enrolled 83 patients with LLD, 35 of which were non-suicidal and 48 were suicidal, including 26 with only suicidal ideation and 22 with past suicide attempts, for resting-state functional magnetic resonance imaging (MRI). Cross-sample entropy (CSE) analysis …

A Milestone In Epithelial-Mesenchymal Transition, Yutong Sun, Li Ma

Faculty, Staff and Student Publications

No abstract provided.

A Reinforcement Learning (Rl)-Motivated Simulation Framework For Evaluating Vancomycin Dosing Strategies, Bingyu Mao, Ziqian Xie, Laila Rasmy, Masayuki Nigo, Degui Zhi

Faculty, Staff and Student Publications

Achieving and maintaining the therapeutic range in vancomycin treatment is important for optimal outcomes. While guidelines and best practices based on empirical studies exist, the theoretical best dosing strategies under various conditions remain illusive. We developed an RL-based simulation framework using a deep learning two-compartment pharmacokinetic model (PK-RNN-2CM) and introduced the area under the time-concentration curve (AUC) reward score, which translates clinical guidelines into an RL reward. Ground truth time-concentration curves were generated from patient-specific data, and simulated curves were produced under different dosing strategies with optional noise perturbations to mimic real-world settings. Evaluation metrics included 24-hour AUC assessments and …

Registration Of Hyperspectral Images And Mass Spectrometry Data For The Correlation Of Tissue Optical Spectra And Molecular Profiles, Angie T Fei, Douglas W Strand, Jing Wang

Faculty, Staff and Student Publications

Hyperspectral imaging (HSI) is a label-free imaging modality that is emerging for non-invasive detection of various diseases including cancers. HSI provides high-resolution spatial images where each pixel has a spectral curve with numerous wavelength bands from the visible to infrared ranges. The rich spatial and spectral information can be used to discriminate various types of tissues and pathophysiological conditions. However, it can be difficult to explain spectral data with respect to the underline cellular and molecular mechanism. In this study, we developed an approach that registers hyperspectral images and mass spectrometry (MS) data where MS provides tissue molecular profiles. Human …

Refinement Of An Emergency Department-Based, Advance Care Planning Intervention For Patients With Cognitive Impairment And Their Caregivers, Kei Ouchi, Christopher Joshi, Jenson Kaithamattam, Seth A Gale, Gad A Marshall, Alison Pietras, Wei Wang, Edward W Boyer, James A Tulsky, Susan D Block, Dorene Rentz, Mara A Schonberg

Faculty, Staff and Student Publications

Background and objectives: Advance care planning (ACP) conversations are important to provide goal-concordant care (i.e., the care that matches the patient's previously stated goals) near end of life. While 31% of older adults presenting to the emergency department (ED) have dementia, only 39% have previously had ACP conversations. We refined and piloted an ED-based, motivational interview designed to stimulate ACP conversations (ED GOAL) for patients living with cognitive impairment and their caregivers.

Research design and methods: We systematically refined ED GOAL and then conducted an acceptability study in an urban, academic medical center. We prospectively enrolled adults aged 50+ with …

Editorial: Immunological Aspects Of Emerging And Re-Emerging Zoonoses, Wei Wang, Jingxin Li, Yuejin Liang, Wenping Gong

Faculty, Staff and Student Publications

No abstract provided.

Unicentric Castleman Disease: Illustration Of Its Morphologic Spectrum And Review Of The Differential Diagnosis, Siba El Hussein, Andrew G Evans, Hong Fang, Wei Wang, L Jeffrey Medeiros

Faculty, Staff and Student Publications

Context: Unicentric Castleman disease (UCD) is a dynamic entity with a wide spectrum of morphologic findings. UCD can be further subdivided into hyaline-vascular and mixed/plasmacytic variants. Hyaline-vascular UCD has both follicular and interfollicular (stromal) changes, and occasionally these lesions show a skewed representation of either the follicular or stromal compartments. Plasmacytosis is usually minimal in the hyaline-vascular variant. The mixed/plasmacytic variant of UCD is composed of sheets of plasma cells often associated with a variable number of follicles with regressive changes.

Objective: To illustrate the differential diagnosis of UCD, as it is quite broad and includes lymphomas, plasma cell neoplasms, …

Highly Variable Timing Renders Immunotherapy Efficacy And Toxicity Impractical Biomarkers Of One Another In Clinical Practice, Mitchell S Von Itzstein, Yuqiu Yang, Yiqing Wang, David Hsiehchen, Thomas Y Sheffield, Farjana Fattah, Vinita Popat, Murtaza Ahmed, Jade Homsi, Jonathan E Dowell, Sawsan Rashdan, Jay Lohrey, Hans J Hammers, Randall S Hughes, Tao Wang, Yang Xie, David E Gerber

Faculty, Staff and Student Publications

Background: A useful clinical biomarker requires not only association but also a consistent temporal relationship. For instance, chemotherapy-induced neutropenia and epidermal growth-factor inhibitor-related acneiform rash both occur within weeks of treatment initiation, thereby providing information prior to efficacy assessment. Although immune checkpoint inhibitor (ICI)-associated immune-related adverse events (irAE) have been associated with therapeutic benefit, irAE may have delayed and highly variable onset. To determine whether ICI efficacy and irAE could serve as clinically useful biomarkers for predicting each other, we determined the temporal relationship between initial efficacy assessment and irAE onset in a diverse population treated with ICI.

Methods: Using …

Foxp1 And Klf2 Reciprocally Regulate Checkpoints Of Stem-Like To Effector Transition In Car T Cells, Ziang Zhu, Guohua Lou, Xiao-Lu Teng, Haixia Wang, Ying Luo, Wangke Shi, Kiddist Yihunie, Shumeng Hao, Kole Degolier, Chengheng Liao, Huocong Huang, Qing Zhang, Terry Fry, Tao Wang, Chen Yao, Tuoqi Wu

Faculty, Staff and Student Publications

During cancers and infections, self-renewing stem-like CD8+ T cells mediate the response of immunotherapies and replenish terminally exhausted T cells and effector-like T cells. However, the programs governing the lineage choice in chimeric antigen receptor (CAR) T cells are unclear. Here, by simultaneously profiling single-cell chromatin accessibility and transcriptome in the same CAR T cells, we identified heterogeneous chromatin states within CD8+ T cell subsets that foreshadowed transcriptional changes and were primed for regulation by distinct transcription factors. Transcription factors that controlled each CD8+ T cell subset were regulated by high numbers of enhancers and positioned as hubs of gene …

Editorial: Advances And Methods In Mesenchymal Stem Cells, Pamela L Wenzel

Faculty, Staff and Student Publications

No abstract provided.

From Mitochondria To Tumor Suppression: Acat1’S Crucial Role In Gastric Cancer, Wei He, Yanfang Li, Song-Bai Liu, Ying Chang, Shiyuan Han, Xingyu Han, Zixin Ma, Hesham M Amin, Yao-Hua Song, Jin Zhou

Faculty, Staff and Student Publications

Acetyl CoA acetyltransferase 1 (ACAT1), a mitochondrial enzyme, is mainly involved in the formation and decomposition of ketones, isoleucine, and fatty acids. Previous clinical studies showed that mutations in the ACAT1 gene lead to ketoacidosis, Notably the role of ACAT1 in human cancer' pathogenesis varies depending on cancer type, and its specific role in gastric cancer remains largely unknown. In the current study, we found that the expression of ACAT1 in primary late-stage gastric cancer tumor tissues was significantly lower than in early-stage tumors. This observation was further confirmed in high-grade gastric cancer cell line MKN45. The expression of CD44 …

Sample Multiplexing In Cytof: Path To Optimize Single-Cell Proteomic Profiling, Muharrem Muftuoglu, Michael Andreeff

Faculty, Staff and Student Publications

Sample multiplexing significantly enhanced the depth of single-cell proteomic analysis in CyTOF (Cytometry by Time-Of-Flight). New polymer-based chelators have broadened the utility of metal isotopes, enabling improved tagging and simultaneous analysis of multiple samples. These approaches minimize batch effects, streamline experiments, conserve valuable samples, reduce costs, enhance throughput, and increase the accuracy of biological data, thereby facilitating novel discoveries.

Generation Of A Wt1 Conditional Deletion, Nuclear Red Fluorescent Protein Reporter Allele In The Mouse, Jace A Aloway, E Cristy Ruteshouser, Vicki Huff, Richard R Behringer

Faculty, Staff and Student Publications

A Wt1 conditional deletion, nuclear red fluorescent protein (RFP) reporter allele was generated in the mouse by gene targeting in embryonic stem cells. Upon Cre-mediated recombination, a deletion allele is generated that expresses RFP in a Wt1-specific pattern. RFP expression was detected in embryonic and adult tissues known to express Wt1, including the kidney, mesonephros, and testis. In addition, RFP expression and WT1 co-localization was detected in the adult uterine stroma and myometrium, suggesting a role in uterine function. Crosses with Wnt7a-Cre transgenic mice that express Cre in the Müllerian duct epithelium activate Wt1-directed RFP expression in the epithelium of …

Dysregulation Of Epigenetic Modifications In Inborn Errors Of Immunity, Zhongyao Xiao, Rongjing He, Zihan Zhao, Taiping Chen, Zhengzhou Ying

Faculty, Staff and Student Publications

Inborn errors of immunity (IEIs) are a group of typically monogenic disorders characterized by dysfunction in the immune system. Individuals with these disorders experience increased susceptibility to infections, autoimmunity and malignancies due to abnormal immune responses. Epigenetic modifications, including DNA methylation, histone modifications and chromatin remodeling, have been well explored in the regulation of immune cell development and effector function. Aberrant epigenetic modifications can disrupt gene expression profiles crucial for immune responses, resulting in impaired immune cell differentiation and function. Dysregulation of these processes caused by mutations in genes involving in epigenetic modifications has been associated with various IEIs. In …

Monitoring Variations In The Use Of Automated Contouring Software, Kelly A Nealon, Eun Young Han, Stephen F Kry, Callistus Nguyen, Mary Pham, Valerie K Reed, David Rosenthal, Samantha Simiele, Laurence E Court

Faculty, Staff and Student Publications

PURPOSE: Our purpose was to identify variations in the clinical use of automatically generated contours that could be attributed to software error, off-label use, or automation bias.

METHODS AND MATERIALS: For 500 head and neck patients who were contoured by an in-house automated contouring system, Dice similarity coefficient and added path length were calculated between the contours generated by the automated system and the final contours after editing for clinical use. Statistical process control was used and control charts were generated with control limits at 3 standard deviations. Contours that exceeded the thresholds were investigated to determine the cause. Moving …

Author Correction: Neoadjuvant Atezolizumab For Resectable Non-Small Cell Lung Cancer: An Open-Label, Single-Arm Phase Ii Trial, Jamie E Chaft, Filiz Oezkan, Mark G Kris, Paul A Bunn, Ignacio I Wistuba, David J Kwiatkowski, Dwight H Owen, Yan Tang, Bruce E Johnson, Jay M Lee, Gerard Lozanski, Maciej Pietrzak, Michal Seweryn, Woo Yul Byun, Katja Schulze, Alan Nicholas, Ann Johnson, Jessica Grindheim, Stephanie Hilz, David S Shames, Chris Rivard, Eric Toloza, Eric B Haura, Ciaran J Mcnamee, G Alexander Patterson, Saiama N Waqar, Valerie W Rusch, David P Carbone

Faculty, Staff and Student Publications

No abstract provided.

Editorial: Genetic And Cellular Heterogeneity In Tumors, Zishan Wang, Li Ma, Juan Xu, Chunjie Jiang

Faculty, Staff and Student Publications

No abstract provided.

Plain Language Summary Of The Foenix-Cca2 Study: Futibatinib For People With Advanced Bile Duct Cancer, Lipika Goyal, Funda Meric-Bernstam, Antoine Hollebecque, Juan W Valle, Chigusa Morizane, Thomas B Karasic, Thomas A Abrams, Junji Furuse, Robin Katie Kelley, Philippe A Cassier, Heinz-Josef Klümpen, Heung-Moon Chang, Li-Tzong Chen, Josep Tabernero, Do-Youn Oh, Amit Mahipal, Markus Moehler, Yoshito Komatsu, Daniel H Ahn, Robert S Epstein, Abdel-Baset Halim, Volker Wacheck, Yaohua He, Mei Liu, Karim A Benhadji, John A Bridgewater, Foenix-Cca2 Study Investigators

Faculty, Staff and Student Publications

What is this summary about?: This summary describes the results from a phase 2 study called FOENIXCCA2. The study evaluated treatment with futibatinib in people with a rare form of advanced bile duct cancer called intrahepatic cholangiocarcinoma (or iCCA), where the tumors have changes in the structure of a gene called FGFR2. These changes include FGFR2 gene fusions. Bile duct cancer often returns after surgery or cannot be treated by surgery because the tumor has spread, so it requires treatment with chemotherapy. People live for a median of 1 year after their first chemotherapy treatment and 6 months after their …

First-In-Human Phase 1 Study Of The Arginase Inhibitor Incb001158 Alone Or Combined With Pembrolizumab In Patients With Advanced Or Metastatic Solid Tumours, Aung Naing, Kyriakos P Papadopoulos, Michael J Pishvaian, Osama Rahma, Glenn J Hanna, Elena Garralda, Omar Saavedra, Sven Gogov, Howard Kallender, Lulu Cheng, Michael Smith, Xuejun Chen, Emil Kuriakose, Todd Bauer

Faculty, Staff and Student Publications

Objective: The arginase inhibitor INCB001158 was evaluated for safety (primary endpoint) in locally advanced or metastatic solid tumours; pharmacokinetics, pharmacodynamics and efficacy were also assessed.

Methods and analysis: In this non-randomised, open-label, three-part phase 1 study, INCB001158 was orally administered two times per day as monotherapy or in combination with intravenous pembrolizumab 200 mg every 3 weeks. Dose expansion was conducted in tumour-type cohorts (with or without prior anti-PD-1/PD-L1 (programmed death protein 1/programmed death ligand 1) therapy).

Results: A total of 107 patients received INCB001158 50-150 mg two times per day as monotherapy, and 153 patients, including 6 with moderate …

Tumor Treating Fields (Ttfields) For Spinal Metastasis–The Case For Bone Removal And Spinal Implants As Waveguides To Enhance Field Strength At The Target, Claudio E Tatsui, Kristen W Carlson, Chirag B Patel

Faculty, Staff and Student Publications

No abstract provided.

Generation Of Non-Alloreactive Antiviral Central Memory Cd8 Human Veto T Cells For Cell Therapy, Esther Bachar-Lustig, Assaf Lask, Yaki Eidelstein, Noga Or-Geva, Rotem Gidron-Budovsky, Bar Nathansohn-Levy, Matthias Eyrich, Wei-Hsin Liu, Giang Dang, Karla Castro Miranda, Alejandro Ramirez, Indreshpal Kaur, Katayoun Rezvani, Elizabeth Shpall, Richard E Champlin, Arnon Nagler, Avichai Shimoni, Sivan Barnees-Kagan, Yair Reisner

Faculty, Staff and Student Publications

Previous studies in mice demonstrated that CD8 T cells exhibit marked veto activity enhancing engraftment in several models for T cell-depleted bone marrow (TDBM) allografting. To reduce the risk of graft-versus-host disease (GVHD) associated with allogeneic CD8 veto T cells, these studies made use of naive CD8 T cells stimulated against third-party stimulators under cytokine deprivation and subsequent expansion in the presence of IL-15. More recently, it was shown that mouse CD8 veto T cells can be generated by stimulating CD8 memory T cells from ovalbumin immunized mice under cytokine deprivation, using ovalbumin as a third-party antigen. These cells also …

Editorial: Updates On Radiation-Induced Lymphopenia, Pim J J Damen, Steven H Lin, Peter S N Van Rossum

Faculty, Staff and Student Publications

Radiotherapy is a commonly employed and effective treatment for cancer, seeking to achieve an optimal balance between tumor cell death and minimizing damage to healthy tissues. Radiation-induced lymphopenia (RIL) is a common side effect due to the high radiosensitivity of lymphocytes even at low doses (< 1Gy), leading to their direct depletion (1). While the detrimental effects of radiotherapy on lymphocytes have been recognized since 1905, its influence on tumor control and survival has remained largely unclear until recently (2). Moreover, awareness and understanding of the prognostic effects of RIL remain limited in daily clinical practice.

Sudden Unexpected Intrapartum Death And Left Ventricular Noncompaction Involving The Right Ventricle, Giulia Ottaviani, Tobia Tomasello, Francesca Boggio, Letterio Runza, Alessandro Del Gobbo, L Maximilian Buja

Faculty, Staff and Student Publications

Left ventricular noncompaction (LVNC), involving mainly the right ventricle, is a rare form of congenital heart disorder characterized by a developmental arrest in myocardial compaction, resulting in a spongy appearance of the myocardium, mainly of the right ventricle, rarely detected in fetuses. We report the case of a female fetus with a gestational age of 41+4 weeks who came to our attention for intrapartum sudden unexpected death, resulting in stillbirth. The ventricular walls, particularly the right ventricular wall, appeared thick, hypertrabeculated and spongy, leading to the diagnosis of LVNC involving mainly the right ventricle. The atrioventricular node and His bundle …

Chronic Lymphocytic Leukemia: Disease Biology, Stefan Koehrer, Jan A Burger

Faculty, Staff and Student Publications

Background: B-cell receptor (BCR) signaling is crucial for normal B-cell development and adaptive immunity. In chronic lymphocytic leukemia (CLL), the malignant B cells display many features of normal mature B lymphocytes, including the expression of functional B-cell receptors (BCRs). Cross talk between CLL cells and the microenvironment in secondary lymphatic organs results in BCR signaling and BCR-driven proliferation of the CLL cells. This critical pathomechanism can be targeted by blocking BCR-related kinases (BTK, PI3K, spleen tyrosine kinase) using small-molecule inhibitors. Among these targets, Bruton tyrosine kinase (BTK) inhibitors have the highest therapeutic efficacy; they effectively block leukemia cell proliferation and …

Chronic Lymphocytic Leukemia: Novel Perspectives - How To Teach An Old Dog New Tricks, Tamar Tadmor, Jan Burger

Faculty, Staff and Student Publications

No abstract provided.