Medical Specialties Commons^™

Mutational Activation Of The Nrf2 Pathway Upregulates Kynureninase Resulting In Tumor Immunosuppression And Poor Outcome In Lung Adenocarcinoma, Johannes F Fahrmann, Ichidai Tanaka, Ehsan Irajizad, Xiangying Mao, Jennifer B Dennison, Eunice Murage, Julian Casabar, Jeffrey Mayo, Qian Peng, Muge Celiktas, Jody V Vykoukal, Soyoung Park, Ayumu Taguchi, Oliver Delgado, Satyendra C Tripathi, Hiroyuki Katayama, Luisa Maren Solis Soto, Jaime Rodriguez-Canales, Carmen Behrens, Ignacio Wistuba, Samir Hanash, Edwin J Ostrin

Faculty, Staff and Student Publications

Activation of the NRF2 pathway through gain-of-function mutations or loss-of-function of its suppressor KEAP1 is a frequent finding in lung cancer. NRF2 activation has been reported to alter the tumor microenvironment. Here, we demonstrated that NRF2 alters tryptophan metabolism through the kynurenine pathway that is associated with a tumor-promoting, immune suppressed microenvironment. Specifically, proteomic profiles of 47 lung adenocarcinoma (LUAD) cell lines (11 KEAP1 mutant and 36 KEAP1 wild-type) revealed the tryptophan-kynurenine enzyme kynureninase (KYNU) as a top overexpressed protein associated with activated NRF2. The siRNA-mediated knockdown of NFE2L2, the gene encoding for NRF2, or activation of the NRF2 …

Definition Of Germ Layer Cell Lineage Alternative Splicing Programs Reveals A Critical Role For Quaking In Specifying Cardiac Cell Fate, W Samuel Fagg, Naiyou Liu, Ulrich Braunschweig, Karen Larissa Pereira De Castro, Xiaoting Chen, Frederick S Ditmars, Steven G Widen, John Paul Donohue, Katalin Modis, William K Russell, Jeffrey H Fair, Matthew T Weirauch, Benjamin J Blencowe, Mariano A Garcia-Blanco

Faculty, Staff and Student Publications

Alternative splicing is critical for development; however, its role in the specification of the three embryonic germ layers is poorly understood. By performing RNA-Seq on human embryonic stem cells (hESCs) and derived definitive endoderm, cardiac mesoderm, and ectoderm cell lineages, we detect distinct alternative splicing programs associated with each lineage. The most prominent splicing program differences are observed between definitive endoderm and cardiac mesoderm. Integrative multi-omics analyses link each program with lineage-enriched RNA binding protein regulators, and further suggest a widespread role for Quaking (QKI) in the specification of cardiac mesoderm. Remarkably, knockout of QKI disrupts the cardiac mesoderm-associated alternative …

Three-Dimensional Evaluation Of Isodose Radiation Volumes In Cases Of Severe Mandibular Osteoradionecrosis For The Prediction Of Recurrence After Segmental Resection, Haye H Glas, Joep Kraeima, Silke Tribius, Frank K J Leusink, Carsten Rendenbach, Max Heiland, Carmen Stromberger, Ashkan Rashad, Clifton D Fuller, Abdallah S R Mohamed, Stephen Y Lai, Max J H Witjes

Faculty, Staff and Student Publications

Background: Pre-operative margin planning for the segmental resection of affected bone in mandibular osteoradionecrosis (ORN) is difficult. The aim of this study was to identify a possible relation between the received RT dose, exposed bone volume and the progression of ORN after segmental mandibular resection.

Method: Patients diagnosed with grade 3-4 ORN for which a segmental resection was performed were included in the study. Three-dimensional reconstructions of RT isodose volumes were fused with postoperative imaging. The primary outcome was the recurrence of ORN after segmental resection. Subsequently, RT exposed mandibular bone volumes were calculated and the location of the bone …

Tite-Boin12: A Bayesian Phase I/Ii Trial Design To Find The Optimal Biological Dose With Late-Onset Toxicity And Efficacy, Yanhong Zhou, Ruitao Lin, J Jack Lee, Daniel Li, Li Wang, Ruobing Li, Ying Yuan

Faculty, Staff and Student Publications

In the era of immunotherapies and targeted therapies, the focus of early phase clinical trials has shifted from finding the maximum tolerated dose to identifying the optimal biological dose (OBD), which maximizes the toxicity-efficacy trade-off. One major impediment to using adaptive designs to find OBD is that efficacy or/and toxicity are often late-onset, hampering the designs’ real-time decision rules for treating new patients. To address this issue, we propose the model-assisted TITE-BOIN12 design to find OBD with late-onset toxicity and efficacy. As an extension of the BOIN12 design, the TITE-BOIN12 design also uses utility to quantify the toxicity-efficacy trade-off. We …

Gli1 Activates Pro-Fibrotic Pathways In Myelofibrosis Fibrocytes, Taghi Manshouri, Ivo Veletic, Ping Li, C Cameron Yin, Sean M Post, Srdan Verstovsek, Zeev Estrov

Faculty, Staff and Student Publications

Bone marrow (BM) fibrosis was thought to be induced exclusively by mesenchymal stromal cells (MSCs). However, we and others found that neoplastic fibrocytes induce BM fibrosis in myelofibrosis (MF). Because glioma-associated oncogene-1 (GLI1), an effector of the Hedgehog pathway, plays a role in the induction of BM fibrosis, we wondered whether GLI1 affects fibrocyte-induced BM fibrosis in MF. Multiplexed fluorescence immunohistochemistry analysis of MF patients' BM detected high levels of GLI1 in MF fibrocytes compared to MSCs or normal fibrocytes. Immunostaining, RNA in situ hybridization, gene expression analysis, and western immunoblotting detected high levels of GLI1 and GLI1-induced matrix metalloproteases …

Pirtobrutinib Inhibits Wild-Type And Mutant Bruton’S Tyrosine Kinase-Mediated Signaling In Chronic Lymphocytic Leukemia, Burcu Aslan, Gorkem Kismali, Lakesla R Iles, Ganiraju C Manyam, Mary L Ayres, Lisa S Chen, Mihai Gagea, Maria Teresa Sabrina Bertilaccio, William G Wierda, Varsha Gandhi

Faculty, Staff and Student Publications

Pirtobrutinib (LOXO-305), a reversible inhibitor of Bruton's tyrosine kinase (BTK), was designed as an alternative strategy to treat ibrutinib-resistant disease that develops due to C481 kinase domain mutations. The clinical activity of pirtobrutinib has been demonstrated in CLL, but the mechanism of action has not been investigated. We evaluated pirtobrutinib in 4 model systems: first, MEC-1, a CLL cell line overexpressing BTKWT, BTKC481S, or BTKC481R; second, murine models driven by MEC-1 overexpressing BTKWT or BTKC481S; third, in vitro incubations of primary CLL cells; and finally, CLL patients during pirtobrutinib therapy (NCT03740529, ClinicalTrials.gov). Pirtobrutinib inhibited BTK activation as well …

Inhibition Of Mitochondrial Complex I Reverses Notch1-Driven Metabolic Reprogramming In T-Cell Acute Lymphoblastic Leukemia, Natalia Baran, Alessia Lodi, Yogesh Dhungana, Shelley Herbrich, Meghan Collins, Shannon Sweeney, Renu Pandey, Anna Skwarska, Shraddha Patel, Mathieu Tremblay, Vinitha Mary Kuruvilla, Antonio Cavazos, Mecit Kaplan, Marc O Warmoes, Diogo Troggian Veiga, Ken Furudate, Shanti Rojas-Sutterin, Andre Haman, Yves Gareau, Anne Marinier, Helen Ma, Karine Harutyunyan, May Daher, Luciana Melo Garcia, Gheath Al-Atrash, Sujan Piya, Vivian Ruvolo, Wentao Yang, Sriram Saravanan Shanmugavelandy, Ningping Feng, Jason Gay, Di Du, Jun J Yang, Fieke W Hoff, Marcin Kaminski, Katarzyna Tomczak, R Eric Davis, Daniel Herranz, Adolfo Ferrando, Elias J Jabbour, M Emilia Di Francesco, David T Teachey, Terzah M Horton, Steven Kornblau, Katayoun Rezvani, Guy Sauvageau, Mihai Gagea, Michael Andreeff, Koichi Takahashi, Joseph R Marszalek, Philip L Lorenzi, Jiyang Yu, Stefano Tiziani, Trang Hoang, Marina Konopleva

Faculty, Staff and Student Publications

T-cell acute lymphoblastic leukemia (T-ALL) is commonly driven by activating mutations in NOTCH1 that facilitate glutamine oxidation. Here we identify oxidative phosphorylation (OxPhos) as a critical pathway for leukemia cell survival and demonstrate a direct relationship between NOTCH1, elevated OxPhos gene expression, and acquired chemoresistance in pre-leukemic and leukemic models. Disrupting OxPhos with IACS-010759, an inhibitor of mitochondrial complex I, causes potent growth inhibition through induction of metabolic shut-down and redox imbalance in NOTCH1-mutated and less so in NOTCH1-wt T-ALL cells. Mechanistically, inhibition of OxPhos induces a metabolic reprogramming into glutaminolysis. We show that pharmacological blockade of OxPhos combined with …

Making National Cancer Institute-Designated Comprehensive Cancer Center Knowledge Accessible To Community Oncologists Via An Online Tumor Board: Longitudinal Observational Study, Maitri Kalra, Elizabeth Henry, Kelly Mccann, Meghan S Karuturi, Jean G Bustamante Alvarez, Amanda Parkes, Robert Wesolowski, Mei Wei, Sarah S Mougalian, Gregory Durm, Angel Qin, Caitlin Schonewolf, Meghna Trivedi, Avan J Armaghani, Frederick H Wilson, Wade T Iams, Anita A Turk, Praveen Vikas, Michael Cecchini, Sam Lubner, Priyadarshini Pathak, Kristen Spencer, Vadim S Koshkin, Matthew K Labriola, Catherine H Marshall, Katy E Beckermann, Marina N Sharifi, Anthony C Bejjani, Varsha Hotchandani, Samir Housri, Nadine Housri

Faculty, Staff and Student Publications

Background: Expert knowledge is often shared among multidisciplinary academic teams at tumor boards (TBs) across the country, but these conversations exist in silos and do not reach the wider oncology community.

Objective: Using an oncologist-only question and answer (Q&A) website, we sought to document expert insights from TBs at National Cancer Institute-designated Comprehensive Cancer Centers (NCI-CCCs) to provide educational benefits to the oncology community.

Methods: We designed a process with the NCI-CCCs to document and share discussions from the TBs focused on areas of practice variation on theMednet, an interactive Q&A website of over 13,000 US oncologists. The faculty translated …

Platelets Increase The Expression Of Pd-L1 In Ovarian Cancer, Min Soon Cho, Hani Lee, Ricardo Gonzalez-Delgado, Dan Li, Tomoyuki Sasano, Wendolyn Carlos-Alcalde, Qing Ma, Jinsong Liu, Anil K Sood, Vahid Afshar-Kharghan

Faculty, Staff and Student Publications

The interactions between platelets and cancer cells activate platelets and enhance tumor growth. Platelets increase proliferation and epithelial-mesenchymal transition in cancer cells, inhibit anoikis, enhance the extravasation of cancer cells, and protect circulating tumor cells against natural killer cells. Here, we have identified another mechanism by which platelets dampen the immune attack on cancer cells. We found that platelets can blunt the antitumor immune response by increasing the expression of inhibitory immune checkpoint (PD-L1) on ovarian cancer cells in vitro and in vivo. Platelets increased PD-L1 in cancer cells via contact-dependent (through NF-κB signaling) and contact-independent (through TFGβR1/Smad signaling) pathways. …

One-Pot, One-Step Synthesis Of Drug-Loaded Magnetic Multimicelle Aggregates, Chang Soo Kim, Dmitry Nevozhay, Rebeca Romero Aburto, Ashok Pehere, Lan Pang, Rebecca Dillard, Ziqiu Wang, Clayton Smith, Kelsey Boitnott Mathieu, Marie Zhang, John D Hazle, Robert C Bast, Konstantin Sokolov

Faculty, Staff and Student Publications

Lipid-based formulations provide a nanotechnology platform that is widely used in a variety of biomedical applications because it has several advantageous properties including biocompatibility, reduced toxicity, relative ease of surface modifications, and the possibility for efficient loading of drugs, biologics, and nanoparticles. A combination of lipid-based formulations with magnetic nanoparticles such as iron oxide was shown to be highly advantageous in a growing number of applications including magnet-mediated drug delivery and image-guided therapy. Currently, lipid-based formulations are prepared by multistep protocols. Simplification of the current multistep procedures can lead to a number of important technological advantages including significantly decreased processing …

An Observational Retrospective Study Of Adverse Events And Behavioral Outcomes During Pediatric Dental Sedation, Kawtar Zouaidi, Gregory Olson, Helen H Lee, Elsbeth Kalenderian, Muhammad F Walji

Faculty, Staff and Student Publications

Purpose: The purpose of this study was to examine a university-based dental electronic health records (EHR) database to identify sedation-related adverse events (AEs) and assess patients' behavioral outcomes during routine pediatric dental sedations (PDSs) in a dental school clinic.

Methods: A database was screened for patients younger than 18 years old who had received dental sedation in 2019. The qualifying EHRs were then accessed and sedations were reviewed for AEs, which were categorized using a 12-point classification system and the Tracking and Reporting Outcomes of Procedural Sedation Tool. Patient behaviors were assessed using provider progress notes and categorized as presence/ …

Rapid Acceleration Of Kras-Mutant Pancreatic Carcinogenesis Via Remodeling Of Tumor Immune Microenvironment By Pparδ, Yi Liu, Yasunori Deguchi, Daoyan Wei, Fuyao Liu, Micheline J Moussalli, Eriko Deguchi, Donghui Li, Huamin Wang, Lovie Ann Valentin, Jennifer K Colby, Jing Wang, Xiaofeng Zheng, Haoqiang Ying, Mihai Gagea, Baoan Ji, Jiaqi Shi, James C Yao, Xiangsheng Zuo, Imad Shureiqi

Faculty, Staff and Student Publications

Pancreatic intraepithelial neoplasia (PanIN) is a precursor of pancreatic ductal adenocarcinoma (PDAC), which commonly occurs in the general populations with aging. Although most PanIN lesions (PanINs) harbor oncogenic KRAS mutations that initiate pancreatic tumorigenesis; PanINs rarely progress to PDAC. Critical factors that promote this progression, especially targetable ones, remain poorly defined. We show that peroxisome proliferator-activated receptor-delta (PPARδ), a lipid nuclear receptor, is upregulated in PanINs in humans and mice. Furthermore, PPARδ ligand activation by a high-fat diet or GW501516 (a highly selective, synthetic PPARδ ligand) in mutant KRASG12D (KRASmu) pancreatic epithelial cells strongly accelerates PanIN progression to PDAC. This …

Chronic Lymphocytic Leukemia Progression Diagnosis With Intrinsic Cellular Patterns Via Unsupervised Clustering, Pingjun Chen, Siba El Hussein, Fuyong Xing, Muhammad Aminu, Aparajith Kannapiran, John D Hazle, L Jeffrey Medeiros, Ignacio I Wistuba, David Jaffray, Joseph D Khoury, Jia Wu

Faculty, Staff and Student Publications

Identifying the progression of chronic lymphocytic leukemia (CLL) to accelerated CLL (aCLL) or transformation to diffuse large B-cell lymphoma (Richter transformation; RT) has significant clinical implications as it prompts a major change in patient management. However, the differentiation between these disease phases may be challenging in routine practice. Unsupervised learning has gained increased attention because of its substantial potential in data intrinsic pattern discovery. Here, we demonstrate that cellular feature engineering, identifying cellular phenotypes via unsupervised clustering, provides the most robust analytic performance in analyzing digitized pathology slides (accuracy = 0.925, AUC = 0.978) when compared to alternative approaches, such …

Immunogenomic Intertumor Heterogeneity Across Primary And Metastatic Sites In A Patient With Lung Adenocarcinoma, Runzhe Chen, Jun Li, Junya Fujimoto, Lingzhi Hong, Xin Hu, Kelly Quek, Ming Tang, Akash Mitra, Carmen Behrens, Chi-Wan Chow, Peixin Jiang, Latasha D Little, Curtis Gumbs, Xingzhi Song, Jianhua Zhang, Dongfeng Tan, John V Heymach, Ignacio Wistuba, P Andrew Futreal, Don L Gibbons, Lauren A Byers, Jianjun Zhang, Alexandre Reuben

Faculty, Staff and Student Publications

Background: Lung cancer is the leading cause of cancer death, partially owing to its extensive heterogeneity. The analysis of intertumor heterogeneity has been limited by an inability to concurrently obtain tissue from synchronous metastases unaltered by multiple prior lines of therapy.

Methods: In order to study the relationship between genomic, epigenomic and T cell repertoire heterogeneity in a rare autopsy case from a 32-year-old female never-smoker with left lung primary late-stage lung adenocarcinoma (LUAD), we did whole-exome sequencing (WES), DNA methylation and T cell receptor (TCR) sequencing to characterize the immunogenomic landscape of one primary and 19 synchronous metastatic tumors. …

Lncrnas Uc145 And Prkg1-As1 Determine The Functional Output Of Dkk1 In Regulating The Wnt Signaling Pathway In Gastric Cancer, Jung-Ho Yoon, Hyojoo Byun, Cristina Ivan, George A Calin, Dahyun Jung, Sangkil Lee

Faculty, Staff and Student Publications

DKK1 inhibits the canonical Wnt signaling pathway that is known to be involved in various cancers. However, whether DKK1 acts as an oncogene or tumor suppressor gene remains controversial. Furthermore, the DKK1-regulating mechanism in gastric cancer has not yet been defined. The aim of this study was to explore whether the ultraconserved region UC.145 regulates epigenetic changes in DKK1 expression in gastric cancer. Microarray analysis revealed that UC.145 exhibited the highest binding affinity to EZH2, a histone methyltransferase. The effects of UC.145 inactivation were assessed in gastric cancer cell lines using siRNA. The results indicated that UC.145 triggers DKK1 methylation …

Ezh2 Engages Tgfβ Signaling To Promote Breast Cancer Bone Metastasis Via Integrin Β1-Fak Activation, Lin Zhang, Jingkun Qu, Yutao Qi, Yimin Duan, Yu-Wen Huang, Zhifen Zhou, Ping Li, Jun Yao, Beibei Huang, Shuxing Zhang, Dihua Yu

Faculty, Staff and Student Publications

Bone metastases occur in 50-70% of patients with late-stage breast cancers and effective therapies are needed. The expression of enhancer of zeste homolog 2 (EZH2) is correlated with breast cancer metastasis, but its function in bone metastasis hasn't been well-explored. Here we report that EZH2 promotes osteolytic metastasis of breast cancer through regulating transforming growth factor beta (TGFβ) signaling. EZH2 induces cancer cell proliferation and osteoclast maturation, whereas EZH2 knockdown decreases bone metastasis incidence and outgrowth in vivo. Mechanistically, EZH2 transcriptionally increases ITGB1, which encodes for integrin β1. Integrin β1 activates focal adhesion kinase (FAK), which phosphorylates TGFβ receptor type …

Identification Of Biomarkers Of Response To Preoperative Talazoparib Monotherapy In Treatment Naïve Gbrca+ Breast Cancers, Xuan Liu, Zhongqi Ge, Fei Yang, Alejandro Contreras, Sanghoon Lee, Jason B White, Yiling Lu, Marilyne Labrie, Banu K Arun, Stacy L Moulder, Gordon B Mills, Helen Piwnica-Worms, Jennifer K Litton, Jeffrey T Chang

Faculty, Staff and Student Publications

Germline mutations in BRCA1 or BRCA2 exist in ~2-7% of breast cancer patients, which has led to the approval of PARP inhibitors in the advanced setting. We have previously reported a phase II neoadjuvant trial of single agent talazoparib for patients with germline BRCA pathogenic variants with a pathologic complete response (pCR) rate of 53%. As nearly half of the patients treated did not have pCR, better strategies are needed to overcome treatment resistance. To this end, we conducted multi-omic analysis of 13 treatment naïve breast cancer tumors from patients that went on to receive single-agent neoadjuvant talazoparib. We looked …

Pattern Differentiation And Tuning Shift In Human Sensory Cortex Underlie Long-Term Threat Memory, Yuqi You, Lucas R Novak, Kevin J Clancy, Wen Li

Faculty, Staff and Student Publications

The amygdala-prefrontal-cortex circuit has long occupied the center of the threat system 1, but new evidence has rapidly amassed to implicate threat processing outside this canonical circuit 2-4. Through non-human research, the sensory cortex has emerged as a critical substrate for long-term threat memory 5-9, underpinned by sensory cortical pattern separation/completion 10,11 and tuning shift 12,13. In humans, research has begun to associate the human sensory cortex with long-term threat memory 14,15, but the lack of mechanistic insights obscures a direct linkage. Towards that end, …

Characterization Of Retinal Function And Structure In The Mptp Murine Model Of Parkinson's Diseasecharacterization Of Retinal Function And Structure In The Mptp Murine Model Of Parkinson’S Disease, Katie K N Tran, Vickie H Y Wong, Jeremiah K H Lim, Ali Shahandeh, Anh Hoang, David I Finkelstein, Bang V Bui, Christine T O Nguyen

Faculty, Staff and Student Publications

In addition to well characterized motor symptoms, visual disturbances are increasingly recognized as an early manifestation in Parkinson's disease (PD). A better understanding of the mechanisms underlying these changes would facilitate the development of vision tests which can be used as preclinical biomarkers to support the development of novel therapeutics for PD. This study aims to characterize the retinal phenotype of a mouse model of dopaminergic dysfunction and to examine whether these changes are reversible with levodopa treatment. We use a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD to characterize the neurotoxic effects of MPTP on in vivo retinal function (electroretinography, …

Bi-Order Multimodal Integration Of Single-Cell Data, Jinzhuang Dou, Shaoheng Liang, Vakul Mohanty, Qi Miao, Yuefan Huang, Qingnan Liang, Xuesen Cheng, Sangbae Kim, Jongsu Choi, Yumei Li, Li Li, May Daher, Rafet Basar, Katayoun Rezvani, Rui Chen, Ken Chen

Faculty, Staff and Student Publications

Integration of single-cell multiomics profiles generated by different single-cell technologies from the same biological sample is still challenging. Previous approaches based on shared features have only provided approximate solutions. Here, we present a novel mathematical solution named bi-order canonical correlation analysis (bi-CCA), which extends the widely used CCA approach to iteratively align the rows and the columns between data matrices. Bi-CCA is generally applicable to combinations of any two single-cell modalities. Validations using co-assayed ground truth data and application to a CAR-NK study and a fetal muscle atlas demonstrate its capability in generating accurate multimodal co-embeddings and discovering cellular identity.

Central Nervous System Immune Interactome Is A Function Of Cancer Lineage, Tumor Microenvironment, And Stat3 Expression, Hinda Najem, Martina Ott, Cynthia Kassab, Arvind Rao, Ganesh Rao, Anantha Marisetty, Adam M Sonabend, Craig Horbinski, Roel Verhaak, Anand Shankar, Santhoshi N Krishnan, Frederick S Varn, Víctor A Arrieta, Pravesh Gupta, Sherise D Ferguson, Jason T Huse, Gregory N Fuller, James P Long, Daniel E Winkowski, Ben A Freiberg, Charles David James, Leonidas C Platanias, Maciej S Lesniak, Jared K Burks, Amy B Heimberger

Faculty, Staff and Student Publications

BACKGROUND

Immune cell profiling of primary and metastatic CNS tumors has been focused on the tumor, not the tumor microenvironment (TME), or has been analyzed via biopsies.

METHODS

En bloc resections of gliomas (n = 10) and lung metastases (n = 10) were analyzed via tissue segmentation and high-dimension Opal 7-color multiplex imaging. Single-cell RNA analyses were used to infer immune cell functionality.

RESULTS

Within gliomas, T cells were localized in the infiltrating edge and perivascular space of tumors, while residing mostly in the stroma of metastatic tumors. CD163⁺ macrophages were evident throughout the TME of metastatic …

Racial And Ethnic Differences In Genomic Profiling Of Early Onset Colorectal Cancer, David M Hein, Weiye Deng, Marylena Bleile, Syed Ali Kazmi, Brooke Rhead, Francisco M De La Vega, Amy L Jones, Radhika Kainthla, Wen Jiang, Brandi Cantarel, Nina N Sanford

Faculty, Staff and Student Publications

The incidence and mortality of early onset colorectal cancer (EOCRC) is rising; outcomes appear to differ by race and ethnicity. We aimed to assess differences in mutational landscape and gene expression of EOCRC by racial and ethnic groups (non-Hispanic Asian, non-Hispanic Black, non-Hispanic White, White Hispanic) using data from the American Association for Cancer Research Project GENIE (10.2) and University of Texas Southwestern, the latter enriched in Hispanic patients. All statistical tests were 2-sided. Of 1752 EOCRC patients, non-Hispanic Black patients had higher rates of KRAS mutations (60.9%; P = .001, q = 0.015), and non-Hispanic White and non-Hispanic Black …

Evidence Supporting A Role For The Immune Checkpoint Protein B7-H3 In Nk Cell-Mediated Cytotoxicity Against Aml, Anudishi Tyagi, Stanley Ly, Fouad El-Dana, Bin Yuan, Appalaraju Jaggupilli, Sabrina Grimm, Marina Konopleva, Hans-Jörg Bühring, V Lokesh Battula

Faculty, Staff and Student Publications

We observed that the immune checkpoint protein B7-H3 is overexpressed in acute myeloid leukemia (AML) patients with poor treatment outcomes. Inhibition of B7-H3 expression or blocking of its activity using a novel monoclonal antibody (T-1A5) in AML cells significantly enhanced natural killer (NK) cell-mediated cytotoxicity in AML cells in vitro and in vivo. Moreover, a human-mouse chimera of this antibody (ChT-1A5) induced antibody-dependent cell-mediated cytotoxicity (ADCC) in B7-H3+ primary AML cells, but not in normal hematopoietic cells, suggesting the specify of this antibody for AML cells. Epitope mapping studies identified that both T-1A5 and ChT-1A5 antibodies bind to the FG-loop …

A Bayesian Group Sequential Design For Randomized Biosimilar Clinical Trials With Adaptive Information Borrowing From Historical Data, Wen Zhang, Zhiying Pan, Ying Yuan

Faculty, Staff and Student Publications

At the time of developing a biosimilar, the reference product has been on market for years and thus ample data are available on its efficacy and characteristics. We develop a Bayesian adaptive design for randomized biosimilar clinical trials to leverage the rich historical data on the reference product. This design takes a group sequential approach. At each interim, we employ the elastic meta-analytic-predictive (EMAP) prior methodology to adaptively borrow information from the historical data of the reference product to make go/no-go decision based on Bayesian posterior probabilities. In addition, the randomization ratio between the test and reference arms is adaptively …

Iv Sotalol Use In Pediatric And Congenital Heart Patients: A Multicenter Registry Study, Lindsey E Malloy-Walton, Nicholas H Von Bergen, Seshadri Balaji, Peter S Fischbach, Jason M Garnreiter, S Yukiko Asaki, Jeffrey P Moak, Luis A Ochoa, Philip M Chang, Hoang H Nguyen, Akash R Patel, Christa Kirk, Ashley K Sherman, Jennifer N Avari Silva, J Philip Saul

Faculty, Staff and Student Publications

Background There is limited information regarding the clinical use and effectiveness of IV sotalol in pediatric patients and patients with congenital heart disease, including those with severe myocardial dysfunction. A multicenter registry study was designed to evaluate the safety, efficacy, and dosing of IV sotalol. Methods and Results A total of 85 patients (age 1 day-36 years) received IV sotalol, of whom 45 (53%) had additional congenital cardiac diagnoses and 4 (5%) were greater than 18 years of age. In 79 patients (93%), IV sotalol was used to treat supraventricular tachycardia and 4 (5%) received it to treat ventricular arrhythmias. …

Bhlhe40 Regulates The T-Cell Effector Function Required For Tumor Microenvironment Remodeling And Immune Checkpoint Therapy Efficacy, Avery J Salmon, Alexander S Shavkunov, Qi Miao, Nicholas N Jarjour, Sunita Keshari, Ekaterina Esaulova, Charmelle D Williams, Jeffrey P Ward, Anna M Highsmith, Josué E Pineda, Reshma Taneja, Ken Chen, Brian T Edelson, Matthew M Gubin

Faculty, Staff and Student Publications

Immune checkpoint therapy (ICT) using antibody blockade of programmed cell death protein 1 (PD-1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) can provoke T cell-dependent antitumor activity that generates durable clinical responses in some patients. The epigenetic and transcriptional features that T cells require for efficacious ICT remain to be fully elucidated. Herein, we report that anti-PD-1 and anti-CTLA-4 ICT induce upregulation of the transcription factor BHLHE40 in tumor antigen-specific CD8+ and CD4+ T cells and that T cells require BHLHE40 for effective ICT in mice bearing immune-edited tumors. Single-cell RNA sequencing of intratumoral immune cells in BHLHE40-deficient mice revealed differential …

Comparison Of Collaborative Goal Setting With Enhanced Education For Managing Diabetes-Associated Distress And Hemoglobin A1c Levels: A Randomized Clinical Trial, Lechauncy Woodard, Amber B Amspoker, Natalie E Hundt, Howard S Gordon, Brian Hertz, Edward Odom, Anne Utech, Javad Razjouyan, Suja S Rajan, Nipa Kamdar, Jasmin Lindo, Lea Kiefer, Praveen Mehta, Aanand D Naik

Faculty, Staff and Student Publications

IMPORTANCE: Type 2 diabetes is a prevalent and morbid condition. Poor engagement with self-management can contribute to diabetes-associated distress and hinder diabetes control.

OBJECTIVE: To evaluate the implementation and effectiveness of Empowering Patients in Chronic Care (EPICC), an evidence-based intervention to improve diabetes-associated distress and hemoglobin A1c (HbA1c) levels after the intervention and after 6-month maintenance.

DESIGN, SETTING, AND PARTICIPANTS: This hybrid (implementation-effectiveness) randomized clinical trial was performed in Veterans Affairs clinics across Illinois, Indiana, and Texas from July 1, 2015, to June 30, 2017. Participants included adults with uncontrolled type 2 diabetes (HbA1c level >8.0%) who received primary care …

The Genomic Alterations In Glioblastoma Influence The Levels Of Csf Metabolites, Wilfredo De Jesús-Rojas, José Muñiz-Hernández, Francisco Alvarado-Huerta, Jesús M Meléndez-Montañez, Arnaldo J Santos-López, Ricardo A Mosquera

Faculty, Staff and Student Publications

Primary ciliary dyskinesia (PCD) has been linked to more than 50 genes that cause a spectrum of clinical symptoms, including newborn respiratory distress, sinopulmonary infections, and laterality abnormalities. Although the RSPH4A (c.921+3_6delAAGT) pathogenic variant has been related to Hispanic groups with Puerto Rican ancestry, it is uncertain how frequently other PCD-implicated genes are present on the island. A retrospective chart review of n = 127 genetic reports from Puerto Rican subjects who underwent genetic screening for PCD variants was conducted from 2018 to 2022. Of 127 subjects, 29.1% subjects presented PCD pathogenic variants, and 13.4% were homozygous for the RSPH4A …

Overall Survival In Phase 3 Clinical Trials And The Surveillance, Epidemiology, And End Results Database In Patients With Metastatic Colorectal Cancer, 1986-2016: A Systematic Review, Chan Shen, Daniel Tannenbaum, Robert Horn, Jane Rogers, Cathy Eng, Shouhao Zhou, Benny Johnson, Scott Kopetz, Van Morris, Michael Overman, Christine Parseghian, George J Chang, Maria A Lopez-Olivo, Raghav Kanwal, Lee M Ellis, Arvind Dasari

Faculty, Staff and Student Publications

Importance: Phase 3 trials for patients with metastatic colorectal cancer (mCRC) have been conducted with varying designs and often with surrogate end points for overall survival (OS).

Objectives: To critically examine the factors associated with clinically relevant improvement in OS (defined as ≥2 months) in these trials and to evaluate their association with outcomes reflected in Surveillance, Epidemiology, and End Results (SEER) registry data.

Evidence review: Medline, EMBASE, Cochrane, Web of Science, ClinicalTrials.gov, EU Clinical Trials Register, and the International Clinical Trials Registry Platform were searched for phase 3 trials of systemic therapy for patients with mCRC by decade (1986-1996, …

Tumor Immune Microenvironment Of Brain Metastases: Toward Unlocking Antitumor Immunity, Matthew R Strickland, Christopher Alvarez-Breckenridge, Justin F Gainor, Priscilla K Brastianos

Faculty, Staff and Student Publications

UNLABELLED: Brain metastasis (BrM) is a devastating complication of solid tumors associated with poor outcomes. Immune-checkpoint inhibitors (ICI) have revolutionized the treatment of cancer, but determinants of response are incompletely understood. Given the rising incidence of BrM, improved understanding of immunobiologic principles unique to the central nervous system (CNS) and dissection of those that govern the activity of ICIs are paramount toward unlocking BrM-specific antitumor immunity. In this review, we seek to discuss the current clinical landscape of ICI activity in the CNS and CNS immunobiology, and we focus, in particular, on the role of glial cells in the CNS …