Digital Commons Network^™

Development And Characterization Of Orthotopic Patient-Derived Xenograft Models Of Peritoneal Metastatic Mucinous Appendiceal Adenocarcinoma, Ichiaki Ito, Vinay K Pattalachinti, Abdelrahman Mg Yousef, Saikat Chowdhury, Mohammad M Fanaeian, Emaan Haque, Betul Beyza Gunes, Mahmoud Yousef, Emma R Salle, Mohammad A Zeineddine, Shuangxi Ji, Ruonan Li, Wenyi Wang, Beth A Helmink, Melissa W Taggart, Michael G White, Keith F Fournier, Natalie W Fowlkes, John Paul Shen

Faculty, Staff and Student Publications

Background: Appendiceal adenocarcinomas (AAs) are a rare and heterogeneous group of tumors for which few preclinical models exist. The lack of preclinical models of AA has hindered drug development and is a major factor in why AA remains without a single FDA-approved systemic treatment.

Materials and methods: Tumors from 16 patients with appendiceal neoplasms (15 AA and one HAMN) were implanted into flank and peritoneal cavity of immunodeficient mice leading to the successful establishment of 3 AAPDX models. Histological, immunohistochemical, genetic, and transcriptomic comparison of patient and PDX tumors were performed.

Results: Higher tumor grade, peritoneal implantation, and RAS/RAF mutation …

Rhabdoid Tumor Of The Kidney And Soft Tissues: Results From National Wilms Tumor Study-5 And Children's Oncology Group Study Aren0321, James I Geller, Lindsay A Renfro, Paul E Grundy, Elizabeth J Perlman, John A Kalapurakal, Peter F Ehrlich, Jackie Biegel, Vicki Huff, Anne B Warwick, Arnold Paulino, Elizabeth A Mullen, Najat C Daw, Fredric A Hoffer, Zelig Tochner, Kenneth Gow, Eric Gratias, Deborah A Ward, James R Anderson, Conrad V Fernandez, Jeffrey S Dome

Faculty, Staff and Student Publications

Purpose: National Wilms Tumor Study-5 (NWTS-5) and AREN0321 evaluated the outcomes of children with rhabdoid tumor of the kidney (RTK) and malignant rhabdoid tumor of soft tissues (MRT).

Patients and methods: Eligible patients with RTK were enrolled prospectively on NWTS-5 (1995-2002) and treated with carboplatin and etoposide alternating with cyclophosphamide (Regimen RTK). Patients with RTK or MRT were enrolled on AREN0321 (2005-2012) and received vincristine, doxorubicin, and cyclophosphamide alternating with carboplatin, cyclophosphamide, and etoposide (Regimens UH-1 or dose-reduced Revised UH-1). We report event-free survival (EFS) and overall survival (OS) from each study.

Results: Thirty patients received Regimen RTK on NWTS-5; …

An Antibody-Toxin Conjugate Targeting Cd47 Linked To The Bacterial Toxin Listeriolysin O For Cancer Immunotherapy, Benjamin R Schrank, Yifan Wang, Annette Wu, Nhat Tran, Daeyong Lee, Jared Edwards, Kristin Huntoon, Shiyan Dong, Jonghoon Ha, Yifan Ma, Adam J Grippin, Seong Dong Jeong, Abin Antony, Mengyu Chang, Minjeong Kang, Thomas D Gallup, Albert C Koong, Jing Li, Kyuson Yun, Betty Y S Kim, Wen Jiang

Faculty, Staff and Student Publications

Antigen-presenting cells phagocytose tumor cells and subsequently cross-present tumor-derived antigens. However, these processes are impeded by phagocytosis checkpoints and inefficient cytosolic transport of antigenic peptides from phagolysosomes. Here, using a microbial-inspired strategy, we engineered an antibody-toxin conjugate (ATC) that targets the 'don't eat me' signal CD47 linked to the bacterial toxin listeriolysin O from the intracellular bacterium Listeria monocytogenes via a cleavable linker (CD47-LLO). CD47-LLO promotes cancer cell phagocytosis by macrophages followed by LLO release and activation to form pores on phagolysosomal membranes that enhance antigen cross-presentation of tumor-derived peptides and activate cytosolic immune sensors. CD47-LLO treatment in vivo significantly …

Wmh Contributions To Cognitive Impairment: Rationale And Design Of The Diverse Vcid Study, Charles Decarli, Kumar B Rajan, Lee-Way Jin, Jason Hinman, David K Johnson, Danielle Harvey, Myriam Fornage

Faculty, Staff and Student Publications

As awareness of dementia increases, more individuals with minor cognitive complaints are requesting clinical assessment. Neuroimaging studies frequently identify incidental white matter hyperintensities, raising patient concerns about their brain health and future risk for dementia. Moreover, current US demographics indicate that ≈50% of these individuals will be from diverse backgrounds by 2060. Racial and ethnic minority populations bear a disproportionate burden of vascular risk factors magnifying dementia risk. Despite established associations between white matter hyperintensities and cognitive impairment, including dementia, no study has comprehensively and prospectively examined the impact of individual and combined magnetic resonance imaging measures of white matter …

Seq-Scope: Repurposing Illumina Sequencing Flow Cells For High-Resolution Spatial Transcriptomics, Yongsung Kim, Weiqiu Cheng, Chun-Seok Cho, Yongha Hwang, Yichen Si, Anna Park, Mitchell Schrank, Jer-En Hsu, Angelo Anacleto, Jingyue Xi, Myungjin Kim, Ellen Pedersen, Olivia I Koues, Thomas Wilson, Changhee Lee, Goo Jun, Hyun Min Kang, Jun Hee Lee

Faculty, Staff and Student Publications

Spatial transcriptomics technologies aim to advance gene expression studies by profiling the entire transcriptome with intact spatial information from a single histological slide. However, the application of spatial transcriptomics is limited by low resolution, limited transcript coverage, complex procedures, poor scalability and high costs of initial setup and/or individual experiments. Seq-Scope repurposes the Illumina sequencing platform for high-resolution, high-content spatial transcriptome analysis, overcoming these limitations. It offers submicrometer resolution, high capture efficiency, rapid turnaround time and precise annotation of histopathology at a much lower cost than commercial alternatives. This protocol details the implementation of Seq-Scope with an Illumina NovaSeq 6000 …

Elder Mistreatment Within Stroke Family Caregiving, Carina Katigbak, Wesley R Browning, Sean Savitz, Carolyn E Z Pickering

Faculty, Staff and Student Publications

This secondary data analysis sought to identify characteristics associated with mistreatment among chronic stroke survivors who transition to dementia. We examined baseline data from a multi-time series survey study (n = 453; where caregivers of those with stroke n = 107, and those without stroke, n = 346) on caregiving experiences influencing dementia family caregivers’ abusive or neglectful behaviors. Inferential statistical analysis indicated that baseline mistreatment rates were similar across stroke and non-stroke subgroups, though this finding was not significant. Caregiver depression was significantly associated with mistreatment. Multi-morbidity, prescription medication use, and limited mobility were more common among stroke …

Outcomes Of Standard-Risk Multiple Myeloma Patients Who Undergo Upfront Autologous Hematopoietic Stem Cell Transplantation, Oren Pasvolsky, Curtis Marcoux, Zhongya Wang, Denái R Milton, Babar Pal, Mark R Tanner, Qaiser Bashir, Samer Srour, Neeraj Saini, Paul Lin, Jeremy Ramdial, Yago Nieto, Guilin Tang, Naureen Syed, Yosra Aljawai, Hans C Lee, Krina K Patel, Melody R Becnel, Christine Ye, Partow Kebriaei, Sheeba K Thomas, Robert Z Orlowski, Richard E Champlin, Elizabeth J Shpall, Muzaffar H Qazilbash

Faculty, Staff and Student Publications

Patients with multiple myeloma (MM) without high-risk cytogenetic abnormalities are classified as having standard-risk MM (SRMM), and data focusing on their outcomes after autologous hematopoietic stem cell transplantation (autoHCT) are limited. We sought to evaluate survival outcomes for patients with SRMM receiving autoHCT, and to elucidate factors that impact these outcomes. This was a single-center retrospective analysis that included consecutive MM patients who received upfront autoHCT between 2013 and 2021, had available cytogenetic information and had no high-risk chromosomal abnormalities on fluorescence in situ hybridization, defined as t(4;14), t(14;16), del(17p) or 1q21 gain or amplification. A total of 1000 SRMM …

In Pursuit Of Ki-Rads: Toward A Single, Evidence-Based Imaging Classification Of Renal Masses, Stuart G Silverman, Ivan Pedrosa, Nicola Schieda, Vitaly Margulis, Payal Kapur, Matthew S Davenport

Faculty, Staff and Student Publications

Despite the successful application of Imaging Reporting and Data Systems to improve the radiologic description and management of disease in many organs, one does not yet exist for the kidney. Instead, the radiologic approach to the kidney has focused on the Bosniak classification system, which is based on imaging characteristics for cystic renal masses, and detecting macroscopic fat within solid renal masses. Radiologically, cystic and solid renal masses are categorized and evaluated separately because of historical precedent, differences in appearance at imaging, and differences in biologic behavior. However, the World Health Organization classification of renal neoplasms does not support such …

Proteasome Augmentation Mitigates Age-Related Cognitive Decline In Mice, Danitra Parker, Kanisa Davidson, Pawel A Osmulski, Maria Gaczynska, Andrew M Pickering

Faculty, Staff and Student Publications

The aging brain experiences a significant decline in proteasome function. The proteasome is critical for many key neuronal functions including neuronal plasticity, and memory formation/retention. Treatment with proteasome inhibitors impairs these processes. Our study reveals a marked reduction in 20S and 26S proteasome activities in aged mice brains, including in the hippocampus, this is driven by reduced functionality of aged proteasome. The decline in proteasome activity is matched by a decline in 20S proteasome assembly. In contrast, 26S proteasome assembly was found to increase with age, though 26S proteasome activity was still found to decline. Our data suggests that age-related …

Combining Radioembolization And Immune Checkpoint Inhibitors For The Treatment Of Hepatocellular Carcinoma: The Quest For Synergy, Christopher D Malone, Suryansh Bajaj, Aiwu He, Kabir Mody, Ryan M Hickey, Ammar Sarwar, Sunil Krishnan, Tushar C Patel, Beau B Toskich

Faculty, Staff and Student Publications

Hepatocellular carcinoma is a leading and increasing contributor to cancer-related death worldwide. Recent advancements in both liver-directed therapies in the form of yttrium-90 (90Y) radioembolization (RE) and systemic therapy in the form of immune checkpoint inhibitors (ICI) have expanded treatment options for patients with an otherwise poor prognosis. Despite these gains, ICIs and 90Y-RE each have key limitations with low objective response rates and persistent hazard of out-of-field recurrence, respectively, and overall survival remains low. However, each therapy's strength may mitigate the other's weakness, making them potentially ideal partners for combination treatment strategies. This review discusses the scientific and clinical …

Qsp Modeling Shows Pathological Synergism Between Insulin Resistance And Amyloid-Beta Exposure In Upregulating Vcam1 Expression At The Bbb Endothelium, Zengtao Wang, Vaishnavi Veerareddy, Xiaojiao Tang, Kevin J Thompson, Sunil Krishnan, Krishna R Kalari, Karunya K Kandimalla

Faculty, Staff and Student Publications

Type 2 diabetes mellitus (T2DM), characterized by insulin resistance, is closely associated with Alzheimer's disease (AD). Cerebrovascular dysfunction is manifested in both T2DM and AD, and is often considered as a pathological link between the two diseases. Insulin signaling regulates critical functions of the blood-brain barrier (BBB), and endothelial insulin resistance could lead to BBB dysfunction, aggravating AD pathology. However, insulin signaling is intrinsically dynamic and involves interactions among numerous molecular mediators. Hence, a mechanistic systems biology model is needed to understand how insulin regulates BBB physiology and the consequences of its impairment in T2DM and AD. In this study, …

Ensartinib For Advanced Or Metastatic Non-Small-Cell Lung Cancer With Met Exon 14 Skipping Mutations (Embrace): A Multi-Center, Single-Arm, Phase 2 Trial, Yang Xia, Panwen Tian, Mo Zhou, Jun Zhao, Yang Jin, Zhiyuan Guo, Xiuzhen Li, Weina Lu, Da Miao, Yuefei Lu, Wanting Xu, Yongchang Zhang, Xiuning Le, Wen Li

Faculty, Staff and Student Publications

Background: MET exon14 skipping mutations (METex14) is an established actionable driver oncogene of non-small-cell lung cancer (NSCLC). While ensartinib is a known second-generation tyrosine kinase inhibitor with primary activity against ALK translocation, it is also classified as a type Ia MET inhibitor. We have previously shown anti-tumor activity against METex14 positive NSCLC both in vivo and in vitro. The EMBRACE trial aims to evaluate the clinical efficacy and safety of ensartinib for treatment of METex14 positive NSCLC.

Methods: This is a multicenter single arm phase II investigator-initiated study that enrolled METex14 positive lung cancer …

Medical Image Segmentation Assisted With Clinical Inputs Via Language Encoder In A Deep Learning Framework, Hengrui Zhao, Biling Wang, Deepkumar Mistry, Jing Wang, Michael Dohopolski, Daniel Yang, Weiguo Lu, Steve Jiang, Dan Nguyen

Faculty, Staff and Student Publications

Introduction: Auto-segmentation of tumor volumes and organs at risk (OARs) is a critical step in cancer radiotherapy treatment planning, where rapid, precise adjustments to treatment plans are required to match the patient anatomy. Although auto-segmentation has been clinically accepted for most OARs, auto-segmentation of tumor volumes, particularly clinical target volumes (CTVs), remains a challenge. This difficulty arises because images alone are often insufficient to capture the necessary information for accurate delineation of microscopic tumor invasion invisible on the image itself.

Methods: We propose a deep learning-based medical image segmentation framework designed to mimic the clinical process of delineating CTVs and …

A Predictive Chromatin Architecture Nexus Regulates Transcription And Dna Damage Repair, Audesh Bhat, Sonali Bhan, Aindrila Kabiraj, Raj K Pandita, Keneth S Ramos, Sandhik Nandi, Shreya Sopori, Parthas S Sarkar, Arti Dhar, Shruti Pandita, Rakesh Kumar, Chandrima Das, John A Tainer, Tej K Pandita

Faculty, Staff and Student Publications

Genomes are blueprints of life essential for an organism's survival, propagation, and evolutionary adaptation. Eukaryotic genomes comprise of DNA, core histones, and several other nonhistone proteins, packaged into chromatin in the tiny confines of nucleus. Chromatin structural organization restricts transcription factors to access DNA, permitting binding only after specific chromatin remodeling events. The fundamental processes in living cells, including transcription, replication, repair, and recombination, are thus regulated by chromatin structure through ATP-dependent remodeling, histone variant incorporation, and various covalent histone modifications including phosphorylation, acetylation, and ubiquitination. These modifications, particularly involving histone variant H2AX, furthermore play crucial roles in DNA damage …

Impact Of Postprogression Therapies On Overall Survival: Recommendations From The 2023 Kidney Cancer Association Think Tank Meeting, Stephanie A Berg, Salvatore La Rosa, Tian Zhang, Phillip M Pierorazio, Laurence Albiges, Kathryn E Beckermann, Matthew T Campbell, Maria I Carlo, Katie Coleman, Daniel J George, Daniel M Geynisman, Ritchie Johnson, Eric Jonasch, Jodi K Maranchie, Bradley A Mcgregor, Daniel D Shapiro, Eric A Singer, Brian M Shuch, Walter M Stadler, Nizar M Tannir, Yousef Zakharia, Ulka N Vaishampayan, Peter F Thall, Pavlos Msaouel

Faculty, Staff and Student Publications

Modern advances in systemic and localized therapies for patients with renal cell carcinoma (RCC) have significantly improved patients' outcomes. If disease progression occurs after initial treatment, clinicians often have multiple options for a first salvage therapy. Because salvage and initial treatments both may affect overall survival time, and they may interact in unanticipated ways, there is a growing need to determine sequences of initial therapy and first salvage therapy that maximize overall survival while maintaining quality of life. The complexity of this problem grows if a second salvage therapy must be chosen for patients with treatment-resistant disease or a second …

Safety And Antitumor Activity Of A Novel Acd25 Treg Depleter Rg6292 As A Single Agent And In Combination With Atezolizumab In Patients With Solid Tumors, Valentina Gambardella, Michael Ong, Maria E Rodriguez-Ruiz, Jean-Pascal Machiels, Miguel F Sanmamed, Vladimir Galvao, Anna Spreafico, Daniel J Renouf, Stephen J Luen, Rachel Galot, Bernard Doger De Spéville, Emiliano Calvo, Aung Naing, Samira Curdt, Theresa Maria Kolben, Eva Rossmann, Tamara Tanos, Kevin Smart, Maria Amann, Yuying Xie, Linxinyu Xu, Enrique Gomez Alcaide, Nicolas Städler, Nicole Justies, Christophe Boetsch, Vaios Karanikas, Gabriel Schnetzler, Kristoffer S Rohrberg

Faculty, Staff and Student Publications

Purpose: Therapeutic depletion of immunosuppressive regulatory T cells (Treg) may overcome resistance to cancer immunotherapies. RG6292 is an anti-CD25 antibody that preferentially depletes Tregs while preserving effector T-cell functions in preclinical models. The safety, pharmacokinetics, pharmacodynamics, and antitumor efficacy of selective Treg depletion by RG6292 administered as monotherapy or in combination with atezolizumab were evaluated in two phase I studies.

Patients and methods: Adult patients with advanced solid tumors were administered intravenous RG6292, given every 3 weeks alone (study 1: NCT04158583, n = 76) or with 1,200 mg atezolizumab every 3 weeks (study 2: NCT04642365, n = 49). …

American Association Of Physicists In Medicine (Aapm) Chapter Climate Check: Mixed Methods Analysis Of Survey Responses, Ashley J Cetnar, Ghada Aldosary, Meghan C Koo, Holly Lincoln, Angélica Pérez-Andújar, Surendra Prajapati, Samantha J Simiele, Kristi R G Hendrickson

Faculty, Staff and Student Publications

Introduction: The American Association of Physicists in Medicine (AAPM) recently shared results and recommendations from its first Equity, Diversity, and Inclusion (EDI) Climate Survey, which was designed to assess the climate at the workplace, the AAPM organization, and the AAPM regional chapter level. This work further explores the status of EDI at the regional chapter level.

Methods: AAPM's EDI Survey was distributed to 5500 members and had a response rate of 25%. In the survey, three open-ended comment boxes were provided for feedback, including one for regional AAPM members. Sixty-four percent of respondents indicated they were part of a regional …

Encorafenib, Cetuximab And Chemotherapy In Braf-Mutant Colorectal Cancer: A Randomized Phase 3 Trial, Scott Kopetz, Takayuki Yoshino, Eric Van Cutsem, Cathy Eng, Tae Won Kim, Harpreet Singh Wasan, Jayesh Desai, Fortunato Ciardiello, Rona Yaeger, Timothy S Maughan, Elena Beyzarov, Xiaoxi Zhang, Graham Ferrier, Xiaosong Zhang, Josep Tabernero

Faculty, Staff and Student Publications

Encorafenib + cetuximab (EC) is approved for previously treated BRAF V600E-mutant metastatic colorectal cancer (mCRC) based on the BEACON phase 3 study. Historically, first-line treatment of BRAF V600E-mutant mCRC with chemotherapy regimens has had limited efficacy. The phase 3 BREAKWATER study investigated EC+mFOLFOX6 versus standard of care (SOC) in patients with previously untreated BRAF V600E mCRC. The dual primary endpoint of progression-free survival is event driven; data were not mature at data cutoff. BREAKWATER met the other dual primary endpoint of objective response rate, demonstrating significant and clinically relevant improvement in objective response rate (EC+mFOLFOX6: 60.9%; SOC: 40.0%; odds ratio, …

Histology-Grounded Automated Plaque Subtype Segmentation In Intravascular Optical Coherence Tomography, Paul Young, Drew Nolen, Thomas E Milner, Alexandra Gruslova, Deborah Vela, Louis Maximilian Buja, Luis A Diaz Sanmartin, Paul Rad, Marc D Feldman

Faculty, Staff and Student Publications

Background: Intravascular optical coherence tomography (IVOCT) adoption has been limited by the complexity of image interpretation. The interpretation of histologic subtypes beyond lipid, calcium, and fibrous is challenging to human readers. To assist and standardize IVOCT image analysis, we demonstrate an artificial intelligence algorithm based on a histology data set that identifies lipid pools, fibrofatty, calcified lipid, and calcified fibrous in human coronary arteries for the first time.

Methods: Sixty-seven human coronary arteries were imaged with IVOCT within 24 hours after death and then underwent histologic examination. IVOCT images were coregistered and segmented into histologic subtypes: lipid pools, fibrofatty tissue, …

Author Correction: Ctla4 Blockade Abrogates Keap1/Stk11-Related Resistance To Pd-(L)1 Inhibitors, Ferdinandos Skoulidis, Haniel A Araujo, Minh Truong Do, Yu Qian, Xin Sun, Ana Galan Cobo, John T Le, Meagan Montesion, Rachael Palmer, Nadine Jahchan, Joseph M Juan, Chengyin Min, Yi Yu, Xuewen Pan, Kathryn C Arbour, Natalie Vokes, Stephanie T Schmidt, David Molkentine, Dwight H Owen, Regan Memmott, Pradnya D Patil, Melina E Marmarelis, Mark M Awad, Joseph C Murray, Jessica A Hellyer, Justin F Gainor, Anastasios Dimou, Christine M Bestvina, Catherine A Shu, Jonathan W Riess, Collin M Blakely, Chad V Pecot, Laura Mezquita, Fabrizio Tabbó, Matthias Scheffler, Subba Digumarthy, Meghan J Mooradian, Adrian G Sacher, Sally C M Lau, Andreas N Saltos, Julia Rotow, Rocio Perez Johnson, Corinne Liu, Tyler Stewart, Sarah B Goldberg, Jonathan Killam, Zenta Walther, Kurt Schalper, Kurtis D Davies, Mark G Woodcock, Valsamo Anagnostou, Kristen A Marrone, Patrick M Forde, Biagio Ricciuti, Deepti Venkatraman, Eliezer M Van Allen, Amy L Cummings, Jonathan W Goldman, Hiram Shaish, Melanie Kier, Sharyn Katz, Charu Aggarwal, Ying Ni, Joseph T Azok, Jeremy Segal, Lauren Ritterhouse, Joel W Neal, Ludovic Lacroix, Yasir Y Elamin, Marcelo V Negrao, Xiuning Le, Vincent K Lam, Whitney E Lewis, Haley N Kemp, Brett Carter, Jack A Roth, Stephen Swisher, Richard Lee, Teng Zhou, Alissa Poteete, Yifan Kong, Tomohiro Takehara, Alvaro Guimaraes Paula, Edwin R Parra Cuentas, Carmen Behrens, Ignacio I Wistuba, Jianjun Zhang, George R Blumenschein, Carl Gay, Lauren A Byers, Don L Gibbons, Anne Tsao, J Jack Lee, Trever G Bivona, D Ross Camidge, Jhannelle E Gray, Natasha B Leighl, Benjamin Levy, Julie R Brahmer, Marina C Garassino, David R Gandara, Edward B Garon, Naiyer A Rizvi, Giorgio Vittorio Scagliotti, Jürgen Wolf, David Planchard, Benjamin Besse, Roy S Herbst, Heather A Wakelee, Nathan A Pennell, Alice T Shaw, Pasi A Jänne, David P Carbone, Matthew D Hellmann, Charles M Rudin, Lee Albacker, Helen Mann, Zhou Zhu, Zhongwu Lai, Ross Stewart, Solange Peters, Melissa L Johnson, Kwok K Wong, Alan Huang, Monte M Winslow, Michael J Rosen, Ian P Winters, Vassiliki A Papadimitrakopoulou, Tina Cascone, Philip Jewsbury, John V Heymach

Faculty, Staff and Student Publications

No abstract provided.

Guidelines For Minimal Reporting Requirements, Design And Interpretation Of Experiments Involving The Use Of Eukaryotic Dual Gene Expression Reporters (Mindr), Gary Loughran, Dmitry E Andreev, Ilya M Terenin, Olivier Namy, Martin Mikl, Martina M Yordanova, C Joel Mcmanus, Andrew E Firth, John F Atkins, Christopher S Fraser, Zoya Ignatova, Shintaro Iwasaki, Joanna Kufel, Ola Larsson, Sebastian A Leidel, Alexander S Mankin, Marco Mariotti, Marvin E Tanenbaum, Ivan Topisirovic, Nora Vázquez-Laslop, Gabriela Viero, Neva Caliskan, Yiwen Chen, Patricia L Clark, Jonathan D Dinman, Philip J Farabaugh, Wendy V Gilbert, Pavel Ivanov, Jeffrey S Kieft, Oliver Mühlemann, Matthew S Sachs, Ivan N Shatsky, Nahum Sonenberg, Anna-Lena Steckelberg, Anne E Willis, Michael T Woodside, Leos Shivaya Valasek, Sergey E Dmitriev, Pavel V Baranov

Faculty, Staff and Student Publications

Dual reporters encoding two distinct proteins within the same mRNA have had a crucial role in identifying and characterizing unconventional mechanisms of eukaryotic translation. These mechanisms include initiation via internal ribosomal entry sites (IRESs), ribosomal frameshifting, stop codon readthrough and reinitiation. This design enables the expression of one reporter to be influenced by the specific mechanism under investigation, while the other reporter serves as an internal control. However, challenges arise when intervening test sequences are placed between these two reporters. Such sequences can inadvertently impact the expression or function of either reporter, independent of translation-related changes, potentially biasing the results. …

Monte Carlo Modeling Of An Experimental Benchtop L-Shell X-Ray Fluorescence Imaging/Ct System Adopting Two Silicone Drift Detectors, Neerajan Nepal, Amrit Kaphle, Sandun Jayarathna, Sang Hyun Cho

Faculty, Staff and Student Publications

L-shell x-ray fluorescence (XRF) photons induced from gold nanoparticles (GNPs) after being irradiated by an x-ray beam allow for highly sensitive XRF imaging/computed tomography (XFCT) of biological samples containing GNPs at low concentrations on the order of parts-per-million (ppm). The primary goal of this Monte Carlo (MC) study was to investigate the feasibility of upgrading an existing experimental benchtop XRF/XFCT imaging setup adopting a single silicon drift detector (SDD), developed based on the aforementioned concept (often known as L-shell XFCT), by deploying another SDD within the same setup. Specifically, an MC model of the original single SDD L-shell XFCT setup, …

An Inducible Foxl2-Dependent Mouse Model Of Ovarian Adult Type Granulosa Cell Tumor, Jian Li, Thomas Welte, Katherine Calzoncinth, Veena K Vuttaradhi, Allison L Brodsky, Kwong-Kwok Wong, Manu M Sebastian, Barrett Lawson, Charles V Kingsley, R Tyler Hillman

Faculty, Staff and Student Publications

Background: Adult-type granulosa cell tumors (AGCTs) are rare ovarian sex cord/stromal tumors with near-universal hotspot mutations in FOXL2 (c.C402G; p.Cys134Trp). Progress in the treatment of relapsed AGCT has been hindered by the lack of high-fidelity FOXL2-based mouse models. To address this critical unmet need, we created and validated a genetically engineered inducible mouse model of the human FOXL2 mutation that recapitulates the key features of the human disease.

Methods: Gene targeting in embryonic stem cells was used to introduce a Cre-inducible Foxl2C130W allele (mouse equivalent of the human oncogenic mutation) into the endogenous mouse Foxl2 locus. Animals with the Foxl2C130W-FLEx …

Loncastuximab In High-Risk And Heavily Pretreated Relapsed/Refractory Diffuse Large B-Cell Lymphoma: A Realworld Analysis From 21 Us Centers, Viktoriya Zelikson, Ashwath Gurumurthi, Yazeed Sawalha, Kaitlin Annunzio, Aditi Saha, Ning Dong, David Qualls, Behzad Amoozgar, Brad Kahl, John Baird, Pavan Challa, Scott F Huntington, Jennifer Santos, Steven Bair, Mayur Narkhede, Shuning Li, Zachary Frosch, Carrie Ho, Stephen D Smith, Allison Winter, Daniel Landsburg, Fateeha Furqan, Mehdi Hamadani, Katelin Baird, Jason Romancik, Hanan Alharthy, Jennie Law, Leyla Bojanini, Ranjana Advani, Boyu Hu, Patrick Connor Johnson, Natalie S Grover, Mwanasha Merril, Jennifer L Crombie, Nazila Shafagati, Cole Sterling, Loretta J Nastoupil, Narendranath Epperla, Emily C Ayers

Faculty, Staff and Student Publications

Outcomes in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) are poor. Loncastuximab- teserine (Lonca) is an antibody-drug conjugate which was approved by the Food and Drug Administration for the treatment of patients with R/R DLBCL who have received at least two prior lines of therapy, based on the results of the LOTIS-2 trial. However, there are limited data regarding its efficacy in the real-world setting. This retrospective study included 21 US centers and evaluated outcomes of patients with R/R DLBCL treated with Lonca. Our analysis comprises 187 patients with notably higher-risk baseline features compared to those of the …

Molecular Testing For The World Health Organization Classification Of Central Nervous System Tumors: A Review, Craig Horbinski, David A Solomon, Rimas V Lukas, Roger J Packer, Priscilla Brastianos, Patrick Y Wen, Matija Snuderl, Mitchel S Berger, Susan Chang, Maryam Fouladi, Joanna J Phillips, Burt Nabors, Daniel J Brat, Jason T Huse, Kenneth Aldape, Jann N Sarkaria, Matthias Holdhoff, Terry C Burns, Katherine B Peters, Ingo K Mellinghoff, David Arons, Evanthia Galanis

Faculty, Staff and Student Publications

Importance: Molecular techniques, including next-generation sequencing, genomic copy number profiling, fusion transcript detection, and genomic DNA methylation arrays, are now indispensable tools for the workup of central nervous system (CNS) tumors. Yet there remains a great deal of heterogeneity in using such biomarker testing across institutions and hospital systems. This is in large part because there is a persistent reluctance among third-party payers to cover molecular testing. The objective of this Review is to describe why comprehensive molecular biomarker testing is now required for the accurate diagnosis and grading and prognostication of CNS tumors and, in so doing, to justify …

Psychometric Evaluation Of The Scleroderma Skin Questionnaire: A Novel Patient-Reported Outcome For Skin Disease In Patients With Systemic Sclerosis, Jeong Min Yu, John M Vanburen, Angela Child, Jessica S Alvey, Lisa A Mandl, Laura C Pinheiro, Shervin Assassi, Elana J Bernstein, Flavia V Castelino, Lorinda Chung, Luke Evnin, Tracy M Frech, Faye N Hant, Laura K Hummers, Dinesh Khanna, Kimberly S Lakin, Dorota Lebiedz-Odrobina, Yiming Luo, Ashima Makol, Jerry A Molitor, Duncan F Moore, Carrie Richardson, Nora Sandorfi, Ami A Shah, Ankoor Shah, Victoria K Shanmugam, Brian Skaug, Virginia D Steen, Elizabeth R Volkmann, Jessica K Gordon

Faculty, Staff and Student Publications

Objective: We aimed to evaluate the psychometric properties of the Scleroderma Skin Questionnaire (SSQ), a novel patient-reported outcome (PRO) to assess systemic sclerosis (SSc)-related skin symptoms.

Methods: Participants were recruited from the SSc Collaborative National Quality and Efficacy Registry (CONQUER). Internal consistency was determined using Cronbach α and McDonald ω total (ωt). The correlation of the SSQ was assessed with the modified Rodnan skin score (mRSS), physician global assessment (PGA), Scleroderma Health Assessment Questionnaire, 29-item Patient-Reported Outcomes Measurement Information System (PROMIS-29), and patient global assessment to assess criterion, convergent, and divergent validity. Correlations were also assessed between patients' self-reported recall …

Diagnostic Pearls And Pitfalls In The Interpretation Of Small Biopsies And Frozen Sections Of The Pancreatobiliary Tract, Huamin Wang, Olca Basturk

Faculty, Staff and Student Publications

No abstract provided.

Resolving Tissue Complexity By Multimodal Spatial Omics Modeling With Miso, Kyle Coleman, Amelia Schroeder, Melanie Loth, Daiwei Zhang, Jeong Hwan Park, Ji-Youn Sung, Niklas Blank, Alexis J Cowan, Xuyu Qian, Jianfeng Chen, Jiahui Jiang, Hanying Yan, Laith Z Samarah, Jean R Clemenceau, Inyeop Jang, Minji Kim, Isabel Barnfather, Joshua D Rabinowitz, Yanxiang Deng, Edward B Lee, Alexander Lazar, Jianjun Gao, Emma E Furth, Tae Hyun Hwang, Linghua Wang, Christoph A Thaiss, Jian Hu, Mingyao Li

Faculty, Staff and Student Publications

Spatial molecular profiling has provided biomedical researchers valuable opportunities to better understand the relationship between cellular localization and tissue function. Effectively modeling multi-modal spatial omics data is crucial for understanding tissue complexity and underlying biology. Furthermore, improvements in spatial resolution have led to the advent of technologies that can generate spatial molecular data with sub-cellular resolution, requiring the development of computationally efficient methods that can handle the resulting large-scale datasets. MISO (MultI-modal Spatial Omics) is a versatile algorithm for feature extraction and clustering, capable of integrating multiple modalities from diverse spatial omics experiments with high spatial resolution. Its effectiveness is …

Diet-Enhanced Lrg1 Expression Promotes Insulin Hypersecretion And Er Stress In Pancreatic Beta Cells, Desirae D Morales, Jiyoon Ryu, Cong Wei, Jason T Hadley, Maia R Smith, Juli Bai, Juan C Lopez-Alvarenga, Srinivas Mummidi, Ravindranath Duggirala, Jane L Lynch, Feng Liu, Lily Q Dong

Faculty, Staff and Student Publications

Aims/hypothesis: Upregulation of serum leucine-rich α-2-glycoprotein 1 (LRG1) has been implicated in diet-induced obesity and metabolic disorders. However, its specific hormonal actions remain unclear. This study aimed to determine whether diet-enhanced serum LRG1 levels promote hyperinsulinaemia by directly stimulating insulin secretion from pancreatic beta cells.

Methods: Human serum samples were obtained from individuals (both male and female) undergoing plastic surgery. Male C57BL/6 wild-type and Lrg1 whole-body knockout (Lrg1KO) mice were fed a 45% high-fat diet, with serum samples collected every 2 weeks to monitor LRG1 and insulin levels throughout diet-induced obesity. MIN6 beta cells were used to investigate the effects …

Robust Automated Method Of Spatial Resolution Measurement In Radiotherapy Ct Simulation Images, Pavel Govyadinov, Rick R Layman, Tucker Netherton, Raymond Mumme, Aaron K Jones, Laurence E Court, Moiz Ahmad

Faculty, Staff and Student Publications

Background: Variation in imaging protocol, patient positioning, and the presence of artifacts can vary image quality in CT images used for radiotherapy planning. Automated methods for spatial resolution (SR) estimation exist but require further investigation and validation for wider adoption.

Purpose: To validated previously existing algorithm for SR estimation and introduce improvements that make it robust to patient positioning, CT protocol, site, and artifacts.

Method: A reference algorithm based on the previous gold standard was recreated and modified to improve robustness. The algorithms were tested on three different datasets: (1) a cylindrical ACR CT QC phantom scanned using a Siemens …