Digital Commons Network^™

Elevated Serum Bile Acids Predict Poor Liver Outcomes In Children With Alagille Syndrome: Results From The Gala Study Group., Carla Fiorella Murillo Perez, Shannon M. Vandriel, Emmanuel M. Gonzales, Jian-She Wang, Li-Ting Li, Huiyu She, Irena Jankowska, Piotr Czubkowski, Dorota Gliwicz-Miedzińska, Emmanuel Jacquemin, Jérôme Bouligand, Lorenzo D'Antiga, Emanuele Nicastro, Björn Fischler, Henrik Arnell, Susan M. Siew, Michael Stormon, Kathleen M. Loomes, David A. Piccoli, Elizabeth B. Rand, James E. Squires, Saul J. Karpen, Rene Romero, Mureo Kasahara, Zerrin Önal, Étienne Sokal, Tanguy Demaret, Sabina Wiecek, Florence Lacaille, Dominique Debray, Winita Hardikar, Sahana Shankar, Pamela L. Valentino, Shikha S. Sundaram, Noelle H. Ebel, Jeffrey A. Feinstein, Orith Waisbourd-Zinman, Henry C. Lin, Nathalie Rock, Henkjan J. Verkade, M Kyle Jensen, Catalina Jaramillo, Kyung Mo Kim, Seak Hee Oh, Jernej Brecemiclj, Seema Alam, Giuseppe Indolfi, Niviann Blondet, Rima Fawaz, Silvia Nastasio, Pier Luigi Calvo, Gabriella Nebbia, Cigdem Arikan, Catherine Larson-Nath, Andréanne N. Zizzo, Thomas Damgaard Sandahl, Christos Tzivinikos, Nehal M. El-Koofy, Mohamed A. Elmonem, Amal A. Aqul, Wikrom Karnsakul, Pinar Bulut, Nanda Kerkar, Victorien M. Wolters, Amin J. Roberts, Helen M. Evans, Maria Camila Sanchez, Maria Lorena Cavalieri, Deirdre A. Kelly, Jane Hartley, Way Seah Lee, Christina Hajinicolaou, Chatmanee Lertudomphonwanit, Ryan T. Fischer, Jesus Quintero Bernabeu, Ruben E. Quiros-Tejeira, Cristina Targa Ferreira, Elisa Carvalho, John Eshun, Aglaia Zellos, Antal Dezsőfi, Raquel Borges Pinto, Kathleen Schwarz, Maria Rogalidou, Jennifer Garcia, María Legarda Tamara, Marisa Beretta, Quais Mujawar, Ermelinda Santos-Silva, Cristina Molera Busoms, Eberhard Lurz, Cristina Gonçalves, Carolina Jimenez-Rivera, Jesus M. Banales, Richard J. Thompson, Bettina E. Hansen, Binita M. Kamath, Global Alagille Alliance (Gala) Study Group

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND AND AIM: Alagille syndrome (ALGS) is a rare disorder characterised by cholestasis and extrahepatic manifestations. Given the current era of ileal bile acid transporter (IBAT) inhibitor therapies that reduce serum bile acid (SBA) levels, we evaluated whether SBA predicts liver disease outcomes in ALGS.

METHODS: Patients were ascertained from the Global ALagille Alliance (GALA) cohort. A prognostic threshold of SBA 102 μmol/L was assessed as a time-dependent covariate in Cox regression analyses for native liver survival (NLS) and event-free survival (EFS), while adjusting for total bilirubin (TB) levels.

RESULTS: 570 GALA patients were included (348 [61%] male). There was …

Acceptability Of Corticosteroid Use In The Treatment Of Infant Bronchiolitis: Utilizing The Theoretical Framework Of Acceptability To Design Research Instruments, Caroline R. Smetanka

Capstone Experience: Master of Public Health

Bronchiolitis is the leading cause of hospitalization among infants under six months, yet treatment remains largely supportive due to clinical guidelines that discourage pharmacologic intervention. Recent research suggests that bronchiolitis is not a uniform condition, and a subgroup of infants (those classified within “Profile A”) may benefit from targeted corticosteroid therapy. However, these treatments remain outside current clinical guidelines, and their successful adoption depends on stakeholder acceptability. This Capstone project developed and refined four data collection instruments- two questionnaires and two interview guides- designed to assess how healthcare providers and caregivers perceive the acceptability of corticosteroid treatment for Profile A …

Loss Of The Lysosomal Protein Cln3 Triggers C-Abl-Dependent Yap1 Pro-Apoptotic Signaling, Neuza Domingues, Alessia Calcagni', Sofia Freire, Joana Pires, Ricardo Casqueiro, Ivan L Salazar, Niculin Joachim Herz, Tuong Huynh, Katarzyna Wieciorek, Tiago Fleming Outeiro, Henrique Girão, Ira Milosevic, Andrea Ballabio, Nuno Raimundo

Duncan NRI Faculty and Staff Publications

Batten disease is characterized by early-onset blindness, juvenile dementia and death within the second decade of life. The most common genetic cause are mutations in CLN3, encoding a lysosomal protein. Currently, no therapies targeting disease progression are available, largely because its molecular mechanisms remain poorly understood. To understand how CLN3 loss affects cellular signaling, we generated human CLN3 knock-out cells (CLN3-KO) and performed RNA-seq analysis. Our multi-dimensional analysis reveals the transcriptional regulator YAP1 as a key factor in remodeling the transcriptome in CLN3-KO cells. YAP1-mediated pro-apoptotic signaling is also increased as a consequence of CLN3 functional loss in retinal pigment …

Tumor Intrinsic Mettl5 Modulates Atf4 Translation To Prevent T Cell-Induced Ferroptosis In Ovarian Cancer, Jiakai Hou, Cheng-Wei Ju, Nicholas A Egan, Yanjun Wei, Yunfei Wang, Minghao Dang, Tianyi Zhou, Leilei Shi, Ningbo Zheng, Si Chen, Ashley M Guerrero, Xiaofang Liang, Wanfu Wu, Areej Akhtar, Chitra Dhiman, Debanwita Roy Burman, Andro E Gerges, Mason D Flores, Han Li, Li-Sheng Zhang, Marleen Kok, Xiaobo Mao, Linghua Wang, Qin Feng, Yiwen Chen, Sanghoon Lee, Daniel J Mcgrail, Nidhi Sahni, Chuan He, Amir A Jazaeri, Weiyi Peng

Faculty, Staff and Student Publications

Poor clinical responses to immune checkpoint blockade (ICB) observed in ovarian cancer (OC) highlight an unmet need to understand the mechanisms driving immune evasion in this disease. To address this, an integrative analysis is conducted by combining in vitro genome‐wide immune screens, in vivo ICB screens, and clinical data mining, and METTL5 is identified as a crucial OC‐intrinsic factor that promotes immune resistance. Immunologically “cold” OC tumors and poor responders to ICB exhibit elevated METTL5 expression. Mechanistically, knocking out (KO) METTL5 in OC disrupts ATF4 translation by altering 18S rRNA m6A levels, leading to the downregulation of SLC7A11 and SLC3A2 …

Kras Inhibition Activates An Actionable Cd24 "Do Not Eat Me" Signal In Pancreatic Cancer, Yongkun Wei, Minghui Liu, Er-Yen Yen, Jun Yao, Zhenzhen Xun, Phuoc T Nguyen, Xiaofei Wang, Zecheng Yang, Abdelrahman Yousef, Dean Pan, Yanqing Jin, Ching-Fei Li, Madelaine S Theardy, Jangho Park, Yiming Cai, Mitsunobu Takeda, Matthew Vasquez, Elizabeth M Park, David H Peng, Yong Zhou, Hong Zhao, Timothy P Heffernan, Andrea Viale, Huamin Wang, Stephanie S Watowich, Han Liang, Dan Zhao, Ronald A Depinho, Wantong Yao, Haoqiang Ying

Faculty, Staff and Student Publications

KRASG12C inhibitors (G12Ci) have produced encouraging, albeit modest and transient, clinical benefit in pancreatic ductal adenocarcinoma (PDAC). Identifying and targeting resistance mechanisms to G12Ci treatment is therefore crucial. To better understand the function of KRASG12C and possible G12Ci bypass mechanisms, we developed an autochthonous KRASG12C-driven PDAC model. Compared to the classical KRASG12D PDAC model, the G12C model exhibits slower tumor growth, yet similar histopathological and molecular features. Aligned with clinical experience, G12Ci treatment of KRASG12C tumors produced modest impact despite stimulating a ‘hot’ tumor immune microenvironment. Immunoprofiling revealed that CD24, a ‘don’t eat me’ signal, is significantly upregulated on cancer …

Clinical Outcomes Of Adult Patients With Newly Diagnosed Mixed Phenotype Acute Leukemia, Hannah Goulart, Farhad Ravandi, Nicholas J Short, Nitin Jain, Naval Daver, Tapan M Kadia, Courtney Dinardo, Gautam Borthakur, Koichi Takahashi, Naveen Pemmaraju, Fadi G Haddad, Guillermo Montalban Bravo, Yesid Alvarado, Ghayas C Issa, Alex Bataller, Sherry Pierce, Sanam Loghavi, Guilin Tang, Sa A Wang, Beenu Thakral, Elizabeth Shpall, Richard Champlin, Issa Khouri, Partow Kebriaei, Guillermo Garcia-Manero, Koji Sasaki, Elias J Jabbour, Jayastu Senapati

Faculty, Staff and Student Publications

Purpose: Mixed phenotype acute leukemia (MPAL) is a rare clinical entity with historically poor outcomes.

Methods: We conducted a retrospective analysis of adults 18 years and older with newly diagnosed B-cell (B/M) or T-cell/myeloid (T/M) MPAL treated at our institution between 2017 and 2024.

Results: We identified 42 patients (median age 70 years); 20 (48%) had B/M MPAL, and 22 (52%) had T/M MPAL; 57% of patients had adverse risk cytogenetics, and 41% had a TP53 mutation. Sixty-two percent of patients were treated with a hybrid regimen, and 45% of patients received intensive therapy. A composite complete remission (CRc; CR …

Mecom Fusion Partner And Bone Marrow Blast Percentage Influence Outcomes Of Patients With Mecom Rearranged Acute Myeloid Leukaemia, Wei-Ying Jen, Guilin Tang, Eitan Kugler, Jennifer Croden, Koji Sasaki, Alexandre Bazinet, Alex Bataller, Guillermo Montalban-Bravo, Gautam Borthakur, Gokce A Toruner, Sanam Loghavi, Nicholas J Short, Ghayas C Issa, Ian M Bouligny, Sherry Pierce, Uday Popat, Naveen Pemmaraju, Elias Jabbour, Guillermo Garcia-Manero, Kapil Bhalla, Farhad Ravandi, Naval G Daver, Courtney D Dinardo, Hagop M Kantarjian, Tapan M Kadia

Faculty, Staff and Student Publications

MECOM rearrangements (MECOM-r) are acute myeloid leukaemia (AML)-defining, regardless of blast percentage or MECOM fusion partner. We sought to investigate if blast percentage or MECOM-r partner was associated with overall survival (OS). We included 152 adult patients with newly diagnosed MECOM-r and classified blast percentage into < 20% or ≥20% and MECOM-r partner into classic (GATA2::MECOM) or variant (others). Thirty-one per cent had < 20% blasts, with 69% having ≥20%; 57% had classic and 43% variant MECOM-r. Treatment was with intensive chemotherapy (IC) in 41% and low-intensity therapy (LIT) in 59%. Composite complete remission rates were similar between IC (50%) and LIT (48%, p = 0.99). The median OS was 17 months (95% confidence interval [CI], 12-not estimable [NE]) for < 20% blasts, compared with 9 months (95% CI, 6-10) for ≥20% blasts (p <  0.01). On multivariate analysis, ≥20% blasts were associated with worse OS (hazard ratio [HR] 1.9, [95% CI, 1.2-3.2], p <  0.01), independent of age, MECOM-r partner, additional cytogenetic abnormalities, treatment intensity, addition of venetoclax and stem cell transplant (SCT). HR for IC was 2.0 (95% CI, 1.1-3.7, p = 0.03). In < 20% blasts, variant MECOM-r was independently associated with a reduced hazard of death (HR 0.2 [95% CI, 0.1-0.8], p <  0.01). MECOM-r AML is a heterogenous entity; consideration should be given to LIT approaches.

Impact Of Postpartum Diagnosis On Survival Of Women With Inflammatory Breast Cancer, Jennifer H Chen, Rebecca S Slack Tidwell, Megumi Kai, Anthony Lucci, Wendy A Woodward, Helen M Johnson

Faculty, Staff and Student Publications

Background: Postpartum diagnosis of breast cancer confers increased risk of metastasis and death, possibly because of protumorigenic pathways that occur after weaning. We sought to evaluate the impact of postpartum diagnosis on survival in patients with inflammatory breast cancer (IBC).

Methods: We performed a retrospective analysis of patients with nonmetastatic IBC enrolled in a prospective registry (2007-2023). Kruskal-Wallis, χ2, and Fisher exact tests were used to compare between postpartum groups. The Kaplan-Meier method and log-rank tests were used for survival estimates.

Results: Among 320 patients with IBC, 25 (7.8%) were nulliparous, 31 (9.7%) were 0 to 5 years postpartum, 26 …

Individualizing Nsaid Therapy In Axial Spondyloarthritis: N-Of-1 Trials With Bayesian Analysis, Mark C Hwang, Seokhun Kim, Shervin Assassi, Reyna Chavez, Joyce Samuel, Charles Green, Jon Tyson, John Reveille

Faculty, Staff and Student Publications

Objective: Axial spondyloarthritis (axSpA) is a chronic inflammatory disease predominantly affecting the spine and sacroiliac joints. NSAIDs are first-line therapy, but individual responses vary widely. We evaluated the efficacy and patient preference of three NSAIDs (celecoxib, meloxicam and naproxen) through Bayesian N-of-1 clinical trials to optimize axSpA management.

Methods: We conducted N-of-1 trials with 42 patients meeting ASAS criteria for axSpA. Each patient was asked to complete two cycles of randomized double-blind crossover comparisons of the three NSAIDs, each for 4 weeks. The primary end point was the change in the Ankylosing Spondylitis Disease Activity Score (ASDAS). Bayesian analysis assessed …

Relative Biological Effectiveness-Clinical Practice At Us Proton Therapy Centers, Armin Lühr, Radhe Mohan, Anita Mahajan, Helen A Shih, Harald Paganetti

Faculty, Staff and Student Publications

Purpose: Proton therapy, with its high conformality and superior dose distribution, is becoming an increasingly prevalent modality in radiation oncology. Although a generic relative biological effectiveness (RBE) value of 1.1 for treatment planning has been adopted, evidence suggests that RBE varies with dose, linear energy transfer (LET), and biological endpoints. This variation raises concerns about underestimating the RBE-weighted dose, which may significantly impact treatment outcomes. To assess the awareness and management of RBE variability in clinical practice, we conducted a survey among US proton therapy centers.

Materials and methods: The survey consisted of 32 questions grouped into subtopics, such as …

Personalized Risk Prediction For Cancer Survivors: A Generalized Bayesian Semi-Parametric Model Of Recurrent Events With Competing Outcomes, Nam Hoai Nguyen, Seung Jun Shin, Elissa Dodd-Eaton, Jing Ning, Wenyi Wang

Faculty, Staff and Student Publications

Multiple primary cancers are increasingly more frequent due to improved survival of cancer patients. Characteristics of the first primary cancer largely impact the risk of developing subsequent primary cancers. Hence, model-based risk characterization of cancer survivors that captures patient-specific variables is needed for healthcare policy making. We propose a Bayesian semi-parametric framework, where the occurrence processes of the competing cancer types follow independent non-homogeneous Poisson processes and adjust for covariates including the type and age at diagnosis of the first primary. Applying this framework to a historically collected cohort with families presenting a highly enriched history of multiple primary tumors …

Cutting Edge Developments In Bone Oncology – Highlights From The Cancer And Bone Society 2024 Annual Meeting, Deanna N Edwards, Shreya Patel, Gabriel M Pagnotti

Faculty, Staff and Student Publications

The 2024 Annual Conference of the Cancer and Bone Society (CABS), held jointly with the Bone Research Society at the University of Sheffield, highlighted the Society's enduring mission to advance understanding of cancer-bone interactions through collaboration, mentorship, and scientific excellence. Established from the early Cancer Induced Bone Disease meetings and re-emerging as an independent body in 2016, CABS continues to serve as a global community bridging basic, translational, and clinical research. This year's meeting featured a comprehensive scientific program spanning tumor-bone biology, therapeutic innovation, and microenvironmental regulation. Clinical sessions emphasized the evolution of bone-targeted treatments such as bisphosphonates, denosumab, and …

Hemophagocytic Lymphohistiocytosis In A Pediatric Lung Transplant Recipient, Sunil Chickmagalur, Anna Schrader, Dallas Parrish, David Moreno Mcneill, Maria C Gazzaneo, Ernestina Melicoff-Portillo, Nahir Cortes-Santiago

Faculty, Staff and Students Publications

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare complication of solid organ transplantation and is a syndrome of systemic hyperinflammation secondary to dysregulation of the inflammatory response, primarily involving lymphocytes and macrophages. It is often fatal and therefore early recognition and treatment are crucial. Among 11 adult cases of HLH in post-lung transplant cases found in the literature, only one patient survived.

Case: We report the first known pediatric case of HLH following lung transplantation. The patient, a previously healthy adolescent, developed end-stage bullous lung disease secondary to acute respiratory distress syndrome (ARDS) and underwent bilateral lung transplantation. Two months posttransplant, …

Forecasting Chemoradiation Response Midtreatment For High-Grade Gliomas Through Patient-Specific Biology-Based Modeling, David A Hormuth, Maguy Farhat, Bikash Panthi, Holly Langshaw, Mihir D Shanker, Wasif Talpur, Sara Thrower, Jodi Goldman, Sophia Ty, Calliope Custer, Jeanne Kowalski, Thomas E Yankeelov, Caroline Chung

Faculty, Staff and Student Publications

Purpose: The entire course of radiation therapy (RT) for high-grade glioma (HGG) is currently derived from pre-RT magnetic resonance imaging (MRI). Although it is possible to adapt RT during the course of treatment, it is often guided only by anatomical changes to the tumor. This study seeks to determine if a biology-based mathematical model, parameterized by patient-specific, multiparametric MRI (mpMRI) data, can accurately forecast HGG response during RT.

Methods and materials: Twenty one patients with HGG planned for 6 weeks of concurrent RT and chemotherapy were imaged weekly with mpMRI during RT and at 1, 2, and 3 months post-RT. …

Improvement And Maintenance Of Clinical Outcome Assessments In Atopic Dermatitis With Amlitelimab, Andrew Blauvelt, Raj Chovatiya, Joseph F Merola, Stephan Weidinger, Ken Igawa, Ella Brookes, Christine Weber, Jennifer Wang, Cori Gray

Faculty, Staff and Student Publications

Background: Amlitelimab, a fully human, nondepleting, anti-OX40 ligand monoclonal antibody, demonstrated reductions in lesional and pruritic endpoints in adults with moderate-to-severe atopic dermatitis (AD) in phase 2a and 2b trials.

Objectives: Here, we examined the effect and durability of amlitelimab on clinical outcome assessments (COAs) in the randomized STREAM-AD phase 2b trial.

Methods: Adults with moderate-to-severe AD with prior inadequate response to or inadvisability of topical medications received subcutaneous amlitelimab (250 mg with 500-mg loading dose, 250 mg, 125 mg or 62.5 mg) or placebo every 4 weeks in Part 1 (Weeks 0-24; 1:1:1:1:1 randomization). In Part 2, Week 24 …

The Longitudinal Impact Of Radiotherapy On Osseointegrated Hearing Aid Outcomes And Complications, Benjamin D Lovin, Mike Hernandez, Paul W Gidley, Karine Al Feghali, Jack Phan, Catherine Wang, Congjun Wang, Dianna Roberts, Marc-Elie Nader

Faculty, Staff and Student Publications

Objective: To evaluate the impact of radiotherapy on osseointegrated hearing aids (OIHA) complications.

Methods: Retrospective review of percutaneous OIHA performed from 2006 to 2021 at an academic institution. Implant and abutment-related complications were evaluated and stratified by radiation parameters. Main outcome measures were abutment, implant, and major complications assessed using the modified Holgers and IPS grading scales.

Results: Total of 190 OIHA were included; 124 (65%) were placed in bones that previously or subsequently received radiation. Total of 84 (44%) OIHA experienced at least one complication at mean 43.3 months. Radiation cohort had greater rates of having any complication (p …

Smart Spatial Omics (S2-Omics) Optimizes Region Of Interest Selection To Capture Molecular Heterogeneity In Diverse Tissues, Musu Yuan, Kaitian Jin, Hanying Yan, Amelia Schroeder, Chunyu Luo, Sicong Yao, Bernhard Dumoulin, Jonathan Levinsohn, Tianhao Luo, Jean R Clemenceau, Inyeop Jang, Minji Kim, Yunhe Liu, Minghua Deng, Emma E Furth, Parker Wilson, Anupma Nayak, Idania Lubo, Luisa Maren Solis Soto, Linghua Wang, Jeong Hwan Park, Katalin Susztak, Tae Hyun Hwang, Mingyao Li

Faculty, Staff and Student Publications

Spatial omics technologies have transformed biomedical research by enabling high-resolution molecular profiling while preserving the native tissue architecture. These advances provide unprecedented insights into tissue structure and function. However, the high cost and time-intensive nature of spatial omics experiments necessitate careful experimental design, particularly in selecting regions of interest (ROIs) from large tissue sections. Currently, ROI selection is performed manually, which introduces subjectivity, inconsistency and a lack of reproducibility. Previous studies have shown strong correlations between spatial molecular patterns and histological features, suggesting that readily available and cost-effective histology images can be leveraged to guide spatial omics experiments. Here we …

The Deubiquitinating Enzyme Cezanne Stabilizes Brca1 By Counteracting Apc/C And Ube2s-Dependent Lys11-Linked Ubiquitination, Longqiang Wang, Xiao Wu, Atanu Paul, Jun Yao, Bin Wang

Faculty, Staff and Student Publications

The breast and ovarian tumor suppressor BRCA1 is a cell cycle-regulated protein and tumors with reduced BRCA1 protein level may share molecular features of BRCA1-mutant tumor and respond to PARPi therapy. Here, we identify that BRCA1 protein stability is controlled through ubiquitin lysine 11 (K11)-linkage modification under the regulation of Cezanne deubiquitinating enzyme, APC/C E3 ligase, and Ube2S E2 conjugating enzyme in a cell cycle-dependent manner. Cezanne-deficiency leads to increased BRCA1 K11-ubiquitination, decreased BRCA1 protein level, and increased cellular sensitivity to PARPi. The BRCA1 K11-linked ubiquitination is carried out through a degron on BRCA1 that is recognized by APC/C cofactor …

Inhibiting Monocyte Migration Reduces Arterial Thrombosis And Facilitates Thrombolysis, Hee Jeong Jang, Jiwon Kim, Ha Kim, Taesu Kim, Jinyong Chung, Sebastian Cremer, Marvin Krohn-Grimberghe, Eo Jin Kim, Dawid Schellingerhout, Matthias Nahrendorf, Dong-Eog Kim

Faculty, Staff and Student Publications

Background: Monocytes contribute to the initiation and propagation of venous thrombosis. Little is known about the roles monocytes play in arterial thrombosis, the cause of stroke and myocardial infarction.

Methods: We investigated how CCR2 (CC chemokine receptor 2) knockout (-/-)-mediated monocyte deficiency affects platelet function, blood coagulation, thrombus volume, and thrombolytic susceptibility in 666 male mice with FeCl3-mediated carotid arterial thrombosis, including 365 C57BL/6 wild type (WT) mice, 295 CCR2-/- mice, and 6 CX3CR1-GFP (CX3C chemokine receptor 1-green fluorescent protein) mice.

Results: Intravital microscopy and flow cytometry showed that both neutrophils and monocytes were recruited to the acute arterial thrombus, …

Profiling The Preclinical Pharmacokinetics And Biodistribution Of A Platinum(Iv)-Based Oxaliplatin Prodrug Oxalitex And Their Significance To Antitumor Response, Guangan He, Gregory D Thiabaud, Kathryn A Shelton, Luke J Segura, Jonathan F Arambula, Jonathan L Sessler, Rick A Finch, Zahid H Siddik

Faculty, Staff and Student Publications

OxaliTEX (NOVO-111) is a novel gadolinium(III) texaphyrin-platinum(IV) complex that is under development for clinical trials. It was designed as a prodrug of oxaliplatin (1,2-diaminocyclohexane-platinum(II) oxalate) tethered to a tumor-affinic texaphyrin moiety to improve drug delivery to the tumor. However, oxaliTEX was not only more effective as an antitumor agent but also better tolerated in mice. To appreciate this higher therapeutic index and advance its preclinical development, studies were undertaken to profile its plasma pharmacokinetics, distribution to tumor and normal tissues, and pharmacodynamics of the p53/p21 molecular pathway. Nude mice, with or without a subcutaneous colorectal HCT-116 xenograft harboring a phenotypically …

Experimental Design And Control Methods For Dose Rate Optimization In A Synchrotron-Based Proton Therapy Beamline, Jason Tang, Daniel Liu, Jacob Mathew, Sabrina Campelo, Lawrence Bronk, Paige Taylor, Yuting Li, Fada Guan

Faculty, Staff and Student Publications

Background: Ultra-high dose rate radiotherapy (typically defined >40 Gy/s) has shown promise for enhanced normal tissue sparing while maintaining tumor control, termed the FLASH effect when this biological response is observed. However, precise dose rate control remains a technical challenge in proton therapy systems, particularly for research applications investigating dose rate effects.

Purpose: To develop and validate a passive beam modulation technique using tungsten scatterers for controllable dose rate adjustment in a synchrotron-based proton therapy beamline without modifying accelerator parameters.

Methods: We investigated dose rate modulation using tungsten foils of varying thicknesses (0.1-3.5 mm) positioned upstream in an 87.2 MeV …

Activity-Dependent Transit Dose Assessment In 192ir High-Dose-Rate Brachytherapy Surface Applicator Using Gafchromictm Ebt4 Film, Daniel Liu, Emily Draeger, Christopher J Tien, Fada Guan

Faculty, Staff and Student Publications

Purpose: To characterize the newly released GafChromicTM EBT4 film for transit dose measurement in high-dose rate brachytherapy (HDR-BT) surface applicators and to systematically investigate the relationship between transit dose and 192Ir source activity.

Methods: EBT4 film was used to measure dose at 3 mm depth from a horizontally oriented Leipzig-style surface applicator connected to a 192Ir HDR-BT remote afterloading unit. Transit dose was systematically characterized across eight different source activities ranging from 3.372 to 9.716 Ci (13,724 U to 39,544 U) using measurements with seven nominal dwell times (5-100 seconds, scaled to 10 Ci (40,700 U)). Transit dose was derived …

Utility Of Serum Matrix Metalloproteinase-7 As A Biomarker In Cholestatic Infants With Congenital Heart Disease, Sindhu Pandurangi, Michael E Kim, Nicolas Noriega, Bradley Conant, Jangdong Seo, Reena Mourya, Pranavkumar Shivakumar, Anna L Peters, Andrew Misfeldt, Meghan Chlebowski

Faculty, Staff and Student Publications

Background: Matrix metalloproteinase 7 (MMP-7) is a novel biomarker for diagnosis of biliary atresia (BA), the most common cholestatic liver disease in infancy. There is a pressing need to determine the utility of MMP-7 levels in infants with congenital heart disease (CHD) to avoid unnecessary invasive diagnostic procedures in this high-risk population. We investigated the utility of MMP-7 in discriminating BA from non-BA cholestasis in infants with CHD and whether MMP-7 elevation was present in infants requiring treatment for clinically significant PH.

Methods: This is a single-center cross-sectional study including infants < 180 days of age with cholestasis and serum MMP-7 levels collected from 2019 to 2023. Demographic data and descriptive statistics were summarized with medians with interquartile ranges and frequencies with percentages. Median MMP-7 levels were assessed via Wilcoxon rank-sum test.

Results: A total of 149 patients were included. Patients …

Pancreatic Cancer-Related Diabetes And Type 2 Diabetes Differ In Multiple Aspects Of Glucose Homeostasis, Frederico G S Toledo, Yisheng Li, Fuchenchu Wang, Melena D Bellin, Randall Brand, Kenneth Cusi, William Fisher, Yogish C Kudva, Walter G Park, Zeb I Saeed, Dhiraj Yadav, Robert V Considine, Sarah C Graham, Dana K Andersen, Jose Serrano, Mark O Goodarzi, Phil A Hart

Faculty, Staff and Student Publications

Aims/hypothesis: Pancreatic ductal adenocarcinoma-related diabetes mellitus (PDAC-DM) is a paraneoplastic syndrome with a poorly understood pathophysiology. PDAC-DM is often clinically confused with type 2 diabetes, resulting in delayed cancer detection and poorly individualised hyperglycaemia treatment. We investigated whether these forms of diabetes can be distinguished at the metabolic level.

Methods: Adults with either cancer treatment-naive PDAC-DM (n=28) or type 2 diabetes (n=97), and with diabetes onset within 3 years, underwent mixed-meal tolerance tests to investigate glucose metabolism. Outcomes included insulin sensitivity (Matsuda index), insulin secretion (insulinogenic index), beta cell function (oral disposition index), insulin clearance, and postprandial glucagon, glucagon-like peptide-1 …

The Role Of Neutrophils In Vasospasm And Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage: Is It Time For A Sah Clinical Trial Targeting Neutrophils?, William W Wroe, Hussein A Zeineddine, Spiros L Blackburn, Jaroslaw Aronowski, Devin W Mcbride

Faculty, Staff and Student Publications

Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating neurological disease, and one of the primary drivers of morbidity after aneurysm rupture is the phenomenon of delayed cerebral ischemia (DCI). Significant knowledge has been gained over the past two decades of the impact of neuroinflammation in DCI; and neutrophils are now believed to play a major role. There is significant human subject data showing the rise of neutrophil related inflammatory markers and neutrophil's association with poor outcome after aSAH, but as of yet no trials involving human subjects have been done specifically targeting neutrophils. There is however a growing body of evidence …

Sars-Cov-2 Rna-Binding Protein Suppresses Extracellular Mirna Release, Hyejin Mun, Chang Hoon Shin, Qingxuan Fei, Andrea Estefania Lopez Giraldo, Kyoung-Min Choi, Ji Won Lee, Kyungmin Kim, Kyung-Won Min, Leilei Shi, Mark T Bedford, Dong-Chan Kim, Yoo Lim Chun, Seonghyun Ryu, Dongin Kim, Jeong Ho Chang, Ryan T Westrope, Michelle Shay, Edward Nguyen, Junho K Hur, Abigail Agyenda, Nam Chul Kim, Sung-Ung Kang, Woonghee Lee, Je-Hyun Yoon

Faculty, Staff and Student Publications

SARS-CoV-2 is the betacoronavirus causing the COVID-19 pandemic. Although the SARS-CoV-2 genome and transcriptome were reported previously, the function of individual viral proteins is largely unknown. Utilizing biochemical and molecular biology methods, we identified that four SARS-CoV-2 RNA-binding proteins (RBPs) regulate the host RNA metabolism by direct interaction with mature miRNA let-7b revealed by Nuclear Magnetic Resonance spectroscopy (NMR). SARS-CoV-2 RBP Nsp9 primarily binds mature miRNA let-7b, a direct ligand of the Toll-like Receptor 7 (TLR7), one of the potential SARS-CoV-2 therapeutics. Nsp9 suppresses host gene expression possibly by promoting let-7b-mediated silencing of a cellular RNA polymerase, POLR2D. In addition, …

Normalization Of Temperature Effects For Quality Assurance Of Quantitative Prostate Apparent Diffusion Coefficient Imaging Across Multiple Sites, Ken-Pin Hwang, Joshua Yung, R Jason Stafford, Caroline Chung, Aradhana M Venkatesan

Faculty, Staff and Student Publications

Background: Apparent Diffusion Coefficient (ADC) as measured by diffusion weighted imaging is known to negatively correlate with prostate tumor aggressiveness. Heterogeneity in system and protocol performance causes potential variability in ADC acquired across a large scanner network, prompting a need to evaluate quantitative ADC from a prostate-specific MR diffusion protocol as part of quality assurance (QA). Due to the temperature dependence of ADC, repeatability and reproducibility assessments typically require phantoms to maintain a temperature of 0°C, imposing a considerable burden when assessing large numbers of scanners.

Purpose: To develop a QA procedure at room temperature for assessing the reproducibility of …

Addressing Controversy In Fusobacterium Nomenclature: What Exactly Does “F Nucleatum” Refer To?, Martha A Zepeda-Rivera, Floyd E Dewhirst, Susan Bullman, Christopher D Johnston

Faculty, Staff and Student Publications

The F. nucleatum group (sensu lato) is historically composed of four subspecies (F. nucleatum subsp. animalis, F. nucleatum subsp. nucleatum, F. nucleatum subsp. polymorphum, F. nucleatum subsp. vincentii). Although F. nucleatum sensu lato members are typically associated with oral disease, they have recently been shown to disseminate to the gastrointestinal tract and are associated with adverse health conditions such as inflammatory bowel disease and colorectal cancer (CRC). A growing debate over the nomenclature applied to Fusobacterium taxonomy has resulted in different names for these lineages, shifting them from their historic subspecies designations to …

Fusobacterium Sphaericum Sp Nov, Isolated From A Human Colon Tumor Adheres To Colonic Epithelial Cells And Induces Il-8 Secretion, Martha A Zepeda-Rivera, Yannick Eisele, Alexander Baryiames, Hanrui Wu, Claudia Mengoni, Gianmarco Piccinno, Elsa F Mcmahon, Kaitlyn D Lacourse, Dakota S Jones, Hans Hauner, Samuel S Minot, Nicola Segata, Floyd E Dewhirst, Christopher D Johnston, Susan Bullman

Faculty, Staff and Student Publications

Cancerous tissue is a largely unexplored microbial niche that provides a unique environment for the colonization and growth of specific bacterial communities, and with it, the opportunity to identify novel bacterial species. Here, we report distinct features of a novel Fusobacterium species, F. sphaericum sp. nov. (Fs), isolated from primary colon adenocarcinoma tissue. We acquire the complete closed genome and associated methylome of this organism and phylogenetically confirm its classification into the Fusobacterium genus, with F. perfoetens as its closest neighbor. Fs is phenotypically and genetically distinct, with morphological analysis revealing its coccoid shape, that while similar to …

A Review Of Engraftment Assessments Following Fecal Microbiota Transplant, Chloe Herman, Bridget M Barker, Thais F Bartelli, Vidhi Chandra, Rosa Krajmalnik-Brown, Mary Jewell, Le Li, Chen Liao, Florencia Mcallister, Khemlal Nirmalkar, Joao B Xavier, J Gregory Caporaso

Faculty, Staff and Student Publications

Fecal Microbiota Transplant (FMT) is a treatment for recurrent Clostridium difficile infections and is being explored for other clinical applications, from alleviating digestive and neurological disorders, to restoring microbiomes impacted by cancer treatment. Quantifying the extent of engraftment following an FMT is important in understanding a recipient's response to treatment. Engraftment and clinical response need to be investigated independently to evaluate an FMT's role (or lack thereof) in achieving a clinical response. Standardized bioinformatics methodologies for quantifying engraftment extent would not only improve assessment and understanding of FMT outcomes, but also facilitate comparison of FMT results and protocols across studies. …