Digital Commons Network^™

An Open Natural Language Processing (Nlp) Framework For Ehr-Based Clinical Research: A Case Demonstration Using The National Covid Cohort Collaborative (N3c), Sijia Liu, Andrew Wen, Liwei Wang, Huan He, Sunyang Fu, Robert Miller, Andrew Williams, Daniel Harris, Ramakanth Kavuluru, Mei Liu, Noor Abu-El-Rub, Dalton Schutte, Rui Zhang, Masoud Rouhizadeh, John D Osborne, Yongqun He, Umit Topaloglu, Stephanie S Hong, Joel H Saltz, Thomas Schaffter, Emily Pfaff, Christopher G Chute, Tim Duong, Melissa A Haendel, Rafael Fuentes, Peter Szolovits, Hua Xu, Hongfang Liu

Faculty, Staff and Student Publications

Despite recent methodology advancements in clinical natural language processing (NLP), the adoption of clinical NLP models within the translational research community remains hindered by process heterogeneity and human factor variations. Concurrently, these factors also dramatically increase the difficulty in developing NLP models in multi-site settings, which is necessary for algorithm robustness and generalizability. Here, we reported on our experience developing an NLP solution for Coronavirus Disease 2019 (COVID-19) signs and symptom extraction in an open NLP framework from a subset of sites participating in the National COVID Cohort (N3C). We then empirically highlight the benefits of multi-site data for both …

Initial Development Of Tools To Identify Child Abuse And Neglect In Pediatric Primary Care, Rochelle F Hanson, Vivienne Zhu, Funlola Are, Hannah Espeleta, Elizabeth Wallis, Paul Heider, Marin Kautz, Leslie Lenert

Faculty, Staff and Student Publications

BACKGROUND: Child abuse and neglect (CAN) is prevalent, associated with long-term adversities, and often undetected. Primary care settings offer a unique opportunity to identify CAN and facilitate referrals, when warranted. Electronic health records (EHR) contain extensive information to support healthcare decisions, yet time constraints preclude most providers from thorough EHR reviews that could indicate CAN. Strategies that summarize EHR data to identify CAN and convey this to providers has potential to mitigate CAN-related sequelae. This study used expert review/consensus and Natural Language Processing (NLP) to develop and test a lexicon to characterize children who have experienced or are at risk …

Gonadotropin-Secreting And Thyrotropin-Secreting Pituitary Adenomas: A Single-Center Experience, Manjiri Karlekar, Chakra Diwaker, Vijaya Sarathi, Anurag Lila, Anima Sharma, Saba Samad Memon, Virendra Patil, Tushar Bandgar

Faculty, Staff and Student Publications

OBJECTIVE: Data regarding rare FPAs from India, a resource limited setting, are limited. We describe a case series of rare FPAs from a single center in western India.

MATERIALS AND METHODS: This was a retrospective case record review of patients diagnosed between January 2010 and July 2022. The diagnosis was based on biochemical(inappropriately elevated serum FSH/LH) and pathologic (positive immunostaining for FSH/LH) features in patients with FGA, and elevated serum thyroid hormones and normal/elevated TSH in patients with TSHomas.

RESULTS: We identified 11 patients with a total of six FGAs (median age 43.5 years, five men, one FGA cosecreting TSH, …

A Multicenter Retrospective Cohort Study To Characterize Patients Hospitalized With Multisystem Inflammatory Syndrome In Adults And Coronavirus Disease 2019 In The United States, 2020-2021, Michael Melgar, Joseph Y Abrams, Shana Godfred-Cato, Ami B Shah, Amit Garg, Andrew Strunk, Mangala Narasimhan, Jonathan Koptyev, Alexandra Norden, David Musheyev, Fahmida Rashid, Rachel Tannenbaum, Rosa M Estrada-Y-Martin, Bela Patel, Siddharth Karanth, Chad J Achenbach, Gavin T Hall, Sara M Hockney, Matthew Caputo, Lilian M Abbo, Laura Beauchamps, Stephen Morris, Renzo O Cifuentes, Annabelle De St Maurice, Douglas S Bell, Kavitha K Prabaker, Fernando J Sanz Vidorreta, Evan Bryant, David K Cohen, Rohith Mohan, Christopher P Libby, Spencer Soohoo, Tristel J Domingo, Angela P Campbell, Ermias D Belay

Faculty, Staff and Student Publications

Background: The diagnosis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated multisystem inflammatory syndrome in adults (MIS-A) requires distinguishing it from acute coronavirus disease 2019 (COVID-19) and may affect clinical management.

Methods: In this retrospective cohort study, we applied the US Centers for Disease Control and Prevention case definition to identify adults hospitalized with MIS-A at 6 academic medical centers from 1 March 2020 to 31 December 2021. Patients MIS-A were matched by age group, sex, site, and admission date at a 1:2 ratio to patients hospitalized with acute symptomatic COVID-19. Conditional logistic regression was used to compare demographic characteristics, …

Reduced Grey Matter Volume In Adolescents With Conduct Disorder: A Region-Of-Interest Analysis Using Multivariate Generalized Linear Modeling, Ru Zhang, R James R Blair, Karina S Blair, Matthew Dobbertin, Jaimie Elowsky, Johannah Bashford-Largo, Ahria J Dominguez, Melissa Hatch, Sahil Bajaj

Faculty, Staff and Student Publications

Background: Conduct disorder (CD) involves a group of behavioral and emotional problems that usually begins during childhood or adolescence. Structural brain alterations have been observed in CD, including the amygdala, insula, ventrolateral and medial prefrontal cortex, anterior cingulate cortex, and fusiform gyrus. The current study developed a multivariate generalized linear model (GLM) to differentiate adolescents with CD from typically developing (TD) adolescents in terms of grey matter volume (GMV).

Methods: The whole-brain structural MRI data were collected from 96 adolescents with CD (mean age = [Formula: see text] years; mean IQ = [Formula: see text]; 63 males) and 90 TD …

Rapid, High Throughput, Automated Detection Of Sars-Cov-2 Neutralizing Antibodies Against Wuhan-Wt, Delta And Omicron Ba1, Ba2 Spike Trimers, Narayanaiah Cheedarla, Hans P Verkerke, Sindhu Potlapalli, Kaleb Benjamin Mclendon, Anamika Patel, Filipp Frank, William Henry O'Sick, Suneethamma Cheedarla, Tyler Jon Baugh, Gregory L Damhorst, Huixia Wu, Daniel Graciaa, Fuad Hudaib, David N Alter, Janetta Bryksin, Eric A Ortlund, Jeanette Guarner, Sara Auld, Sarita Shah, Wilbur Lam, Dawn Mattoon, Joseph M Johnson, David H Wilson, Madhav V Dhodapkar, Sean R Stowell, Andrew S Neish, John D Roback

Faculty, Staff and Student Publications

Traditional cellular and live-virus methods for detection of SARS-CoV-2 neutralizing antibodies (nAbs) are labor- and time-intensive, and thus not suited for routine use in the clinical lab to predict vaccine efficacy and natural immune protection. Here, we report the development and validation of a rapid, high throughput method for measuring SARS-CoV-2 nAbs against native-like trimeric spike proteins. This assay uses a blockade of human angiotensin converting enzyme 2 (hACE-2) binding (BoAb) approach in an automated digital immunoassay on the Quanterix HD-X platform. BoAb assays using Wuhan-WT (vaccine strain), delta (B.1.167.2), omicron BA1 and BA2 variant viral strains showed strong correlation …

Pmca Screening Of Retropharyngeal Lymph Nodes In White-Tailed Deer And Comparisons With Elisa And Ihc, Rebeca Benavente, J Hunter Reed, Mitch Lockwood, Rodrigo Morales

Faculty, Staff and Student Publications

Chronic wasting disease (CWD) is a prion disease affecting cervids. CWD diagnosis is conducted through enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry (IHC) in retropharyngeal lymph nodes. Unfortunately, these techniques have limited sensitivity against the biomarker (CWD-prions). Two in vitro prion amplification techniques, real-time quaking-induced conversion (RT-QuIC) and protein misfolding cyclic amplification (PMCA), have shown promise in detecting CWD-prions in tissues and bodily fluids. Recent studies have demonstrated that RT-QuIC yields similar results compared to ELISA and IHC. Here, we analyzed 1003 retropharyngeal lymph nodes (RPLNs) from Texas white-tailed deer. PMCA detected CWD at a higher rate compared to ELISA/IHC, identified …

Dlx2 Promotes Osteosarcoma Epithelial-Mesenchymal Transition And Doxorubicin Resistance By Enhancing Hoxc8-Cdh2 Axis, Boya Zhang, Xinhui Du, Yichao Fan, Guoxin Qu, Lon Kai Pang, Ruiying Zhao, Weitao Yao

Faculty, Staff and Student Publications

Metastasis and doxorubicin resistance are challenges in the clinical diagnosis and treatment of osteosarcoma, the mechanisms underlying these phenomena remain unclear. In this study, we found that DLX2 is highly expressed in metastatic osteosarcoma and is closely related to clinical prognosis. Knockdown of DLX2 inhibited tumor proliferation and migration in vitro and inhibited tumor growth in vivo. Mechanistically, we found that DLX2 enhanced the repression of CDH2 transcription by binding to HOXC8, thereby promoting the epithelial-mesenchymal transition in osteosarcoma cells. Through subsequent exploration, we found that targeting DLX2/HOXC8 signaling significantly restores the sensitivity of osteosarcoma cells to doxorubicin. In …

Membrane Anchoring Of The Diras3 N-Terminal Extension Permits Tumor Suppressor Function, Xiaowen Liang, Sung Yun Jung, Lon Wolf Fong, Gamze Bildik, Joshua P Gray, Weiqun Mao, Shuxing Zhang, Steven W Millward, Alemayehu A Gorfe, Yong Zhou, Zhen Lu, Robert C Bast

Faculty, Staff and Student Publications

DIRAS3 is an imprinted tumor suppressor gene encoding a GTPase that has a distinctive N-terminal extension (NTE) not found in other RAS proteins. This NTE and the prenylated C-terminus are required for DIRAS3-mediated inhibition of RAS/MAP signaling and PI3K activity at the plasma membrane. In this study, we applied biochemical, biophysical, and computational methods to characterize the structure and function of the NTE. The NTE peptide recognizes phosphoinositides PI(3,4,5)P3 and PI(4,5)P2 with rapid kinetics and strong affinity. Lipid binding induces NTE structural change from disorder to amphipathic helix. Mass spectrometry identified N-myristoylation of DIRAS3. All-atom molecular dynamic simulations predict DIRAS3 …

Candida Auris-Macrophage Cellular Interactions And Transcriptional Response, Pedro Miramón, Andrew W Pountain, Michael C Lorenz

Faculty, Staff and Student Publications

The pathogenic yeast Candida auris represents a global threat of the utmost clinical relevance. This emerging fungal species is remarkable in its resistance to commonly used antifungal agents and its persistence in the nosocomial settings. The innate immune system is one the first lines of defense preventing the dissemination of pathogens in the host. C. auris is susceptible to circulating phagocytes, and understanding the molecular details of these interactions may suggest routes to improved therapies. In this work, we examined the interactions of this yeast with macrophages. We found that macrophages avidly phagocytose C. auris; however, intracellular replication is …

First-Line Selpercatinib Or Chemotherapy And Pembrolizumab In Ret Fusion-Positive Nsclc, Caicun Zhou, Benjamin Solomon, Herbert H Loong, Keunchil Park, Maurice Pérol, Edurne Arriola, Silvia Novello, Baohui Han, Jianying Zhou, Andrea Ardizzoni, M Perez Mak, Fernando C Santini, Yasir Y Elamin, Alexander Drilon, Jürgen Wolf, Nalin Payakachat, Minji K Uh, Deborah Rajakumar, Hongmei Han, Tarun Puri, Victoria Soldatenkova, A Bence Lin, Boris K Lin, Koichi Goto, Libretto-431 Trial Investigators

Faculty, Staff and Student Publications

Background: Selpercatinib, a highly selective potent and brain-penetrant RET inhibitor, was shown to have efficacy in patients with advanced RET fusion-positive non-small-cell lung cancer (NSCLC) in a nonrandomized phase 1-2 study.

Methods: In a randomized phase 3 trial, we evaluated the efficacy and safety of first-line selpercatinib as compared with control treatment that consisted of platinum-based chemotherapy with or without pembrolizumab at the investigator's discretion. The primary end point was progression-free survival assessed by blinded independent central review in both the intention-to-treat-pembrolizumab population (i.e., patients whose physicians had planned to treat them with pembrolizumab in the event that they were …

Circulating Metabolites May Illustrate Relationship Of Alcohol Consumption With Cardiovascular Disease, Yi Li, Mengyao Wang, Xue Liu, Jian Rong, Patricia Emogene Miller, Roby Joehanes, Tianxiao Huan, Xiuqing Guo, Jerome I Rotter, Jennifer A Smith, Bing Yu, Matthew Nayor, Daniel Levy, Chunyu Liu, Jiantao Ma

Faculty, Staff and Student Publications

BACKGROUND: Metabolite signatures of long-term alcohol consumption are lacking. To better understand the molecular basis linking alcohol drinking and cardiovascular disease (CVD), we investigated circulating metabolites associated with long-term alcohol consumption and examined whether these metabolites were associated with incident CVD.

METHODS: Cumulative average alcohol consumption (g/day) was derived from the total consumption of beer, wine, and liquor on average of 19 years in 2428 Framingham Heart Study Offspring participants (mean age 56 years, 52% women). We used linear mixed models to investigate the associations of alcohol consumption with 211 log-transformed plasma metabolites, adjusting for age, sex, batch, smoking, diet, …

Identification Of Cdk1, Pbk, And Chek1 As An Oncogenic Signature In Glioblastoma: A Bioinformatics Approach To Repurpose Dapagliflozin As A Therapeutic Agent, Harold A Chinyama, Li Wei, Ntlotlang Mokgautsi, Bashir Lawal, Alexander T H Wu, Hsu-Shan Huang

Faculty, Staff and Student Publications

Glioblastoma multiforme (GBM) is the most aggressive and lethal primary brain tumor whose median survival is less than 15 months. The current treatment regimen comprising surgical resectioning, chemotherapy with Temozolomide (TMZ), and adjuvant radiotherapy does not achieve total patient cure. Stem cells' presence and GBM tumor heterogeneity increase their resistance to TMZ, hence the poor overall survival of patients. A dysregulated cell cycle in glioblastoma enhances the rapid progression of GBM by evading senescence or apoptosis through an over-expression of cyclin-dependent kinases and other protein kinases that are the cell cycle's main regulatory proteins. Herein, we identified and validated the …

Cytomulate: Accurate And Efficient Simulation Of Cytof Data, Yuqiu Yang, Kaiwen Wang, Zeyu Lu, Tao Wang, Xinlei Wang

Faculty, Staff and Student Publications

Recently, many analysis tools have been devised to offer insights into data generated via cytometry by time-of-flight (CyTOF). However, objective evaluations of these methods remain absent as most evaluations are conducted against real data where the ground truth is generally unknown. In this paper, we develop Cytomulate, a reproducible and accurate simulation algorithm of CyTOF data, which could serve as a foundation for future method development and evaluation. We demonstrate that Cytomulate can capture various characteristics of CyTOF data and is superior in learning overall data distributions than single-cell RNA-seq-oriented methods such as scDesign2, Splatter, and generative models like LAMBDA.

Endoscopic Retrograde Cholangiopancreatography-Related Early Perforations: A Study Of Effects Of Procedure Duration, Complexity, And Endoscopist Experience, Mark Aloysius, Hemant Goyal, Tejas Nikumbh, Niraj James Shah, Ghassan M Hammoud, Pritesh Mutha, Mairin Joseph-Talreja, Savio John, Ganesh Aswath, Vaibhav Wadhwa, Nirav Thosani

Faculty, Staff and Student Publications

BACKGROUND: Perforations (Perf) during endoscopic retrograde cholangiopancreatography (ERCP) are rare (< 1%) but potentially fatal events (up to 20% mortality). Given its rarity, most data is through case series studies from centers or analysis of large databases. Although a meta-analysis has shown fewer adverse events as a composite (bleeding, pancreatitis, Perf) during ERCP performed at high-volume centers, there is very little real-world data on endoscopist and center procedural volumes, ERCP duration and complexity on the occurrence of Perf.

AIM: To study the profile of Perf related to ERCP by center and endoscopist procedure volume, ERCP time, and complexity from a national endoscopic repository.

METHODS: Patients from clinical outcomes research initiative-national endoscopic database (2000-2012) who underwent ERCP were stratified based on the endoscopist and center volume (quartiles), and total procedure duration and complexity grade of the ERCP based on procedure details. The effects of these variables on the Perf that occurred were studied. Continuous variables were compared between Perf and no perforations (NoPerf) using the Mann-Whitney U test …

Internet Analytics Of An Innovative Digital Educational Resource Of Type 1 Diabetes Hellotype1 In Local Languages For People Living With Diabetes Families And Healthcare Professionals In Southeast Asia, Sze May Ng, I V Malene, Thy Khue Nguyen, Khuong Le, Yang Xian Lucas Lim, Ngee Lek, Samantha Seal, Steffen Yun Tange, Azriyanti Anuar Zaini, Taninee Sahakitrungruang, Anne Charlotte Ficheroulle

Faculty, Staff and Student Publications

BACKGROUND: There is minimal data of health outcomes for Type 1 Diabetes (T1D) in Southeast Asia (SEA) where government funding of insulin and blood glucose monitoring either do not exist or is limited. The full impact of Covid-19 pandemic on the national economies of SEA remain unknown. In the midst of the pandemic, in 2021, HelloType1 was developed by Action4Diabetes (A4D), a non-government organisation charity in collaboration with Southeast Asia local healthcare professionals as an innovative digital educational resource platform of T1D in local languages. HelloType1 was launched in Cambodia, Vietnam, Thailand and Malaysia in 2021 to 2022 with Memorandums …

Morphological Comparison Of Residual Ridge In Impression For Removable Partial Denture Between Digital And Conventional Techniques: A Preliminary In-Vivo Study, Yurika Ishioka, Junichiro Wada, Eung-Yeol Kim, Kazuki Sakamoto, Yuki Arai, Natsuko Murakami, Toshiki Yamazaki, Kensuke Takakusaki, Hironari Hayama, Miona Utsumi, Shusuke Inukai, Noriyuki Wakabayashi

Faculty, Staff and Student Publications

Although digital impression using an intraoral scanner (IOS) has been applied for removable partial denture (RPD) fabrication, it is still unclear how the morphology of a residual ridge recorded by digital impression would differ from that recorded by conventional impression. This in vivo study investigated the morphological difference in the recorded residual ridge between digital and conventional impressions. Vertical and horizontal displacements (VD and HD) in residual ridges recorded by digital and conventional impressions were assessed in 22 participants (15 female; mean age 78.2 years) based on the morphology of the tissue surface of in-use RPD. Additionally, the mucosal thickness …

Galectin-3 Cooperates With Cd47 To Suppress Phagocytosis And T-Cell Immunity In Gastric Cancer Peritoneal Metastases, Yibo Fan, Shumei Song, Yuan Li, Shilpa S Dhar, Jiankang Jin, Katsuhiro Yoshimura, Xiaodan Yao, Ruiping Wang, Ailing W Scott, Melissa Pool Pizzi, Jingjing Wu, Lang Ma, George A Calin, Samir Hanash, Linghua Wang, Michael Curran, Jaffer A Ajani

Faculty, Staff and Student Publications

UNLABELLED: The peritoneal cavity is a common site of gastric adenocarcinoma (GAC) metastasis. Peritoneal carcinomatosis (PC) is resistant to current therapies and confers poor prognosis, highlighting the need to identify new therapeutic targets. CD47 conveys a "don't eat me" signal to myeloid cells upon binding its receptor signal regulatory protein alpha (SIRPα), which helps tumor cells circumvent macrophage phagocytosis and evade innate immune responses. Previous studies demonstrated that the blockade of CD47 alone results in limited clinical benefits, suggesting that other target(s) might need to be inhibited simultaneously with CD47 to elicit a strong antitumor response. Here, we found that …

Indices Of Narrative Language Associated With Disability, Norah M Almubark, Gabriela Silva-Maceda, Matthew E Foster, Trina D Spencer

Faculty, Staff and Student Publications

Narratives skills are associated with long-term academic and social benefits. While students with disabilities often struggle to produce complete and complex narratives, it remains unclear which aspects of narrative language are most indicative of disability. In this study, we examined the association between a variety of narrative contents and form indices and disability. Methodology involved drawing 50 K-3 students with Individual Education Programs (IEP) and reported language concerns from a large diverse sample (n = 1074). Fifty typically developing (TD) students were matched to the former group using propensity score matching based on their age, gender, grade, mother’s education, …

Baseline Extracellular Vesicle Mirna-30c And Autophagic Ctcs Predict Chemoradiotherapy Resistance And Outcomes In Patients With Lung Cancer, Diego De Miguel-Perez, Francisco Gabriel Ortega, Rosario Guerrero Tejada, Antonio Martínez-Única, Christine B Peterson, Alessandro Russo, Muthukumar Gunasekaran, Andres F Cardona, Victor Amezcua, Jose Antonio Lorente, Jose Expósito Hernández, Christian Rolfo, Maria Jose Serrano

Faculty, Staff and Student Publications

Concurrent chemoradiotherapy (cCRT) is the mainstay of treatment for patients diagnosed with locally advanced non-small cell lung cancer (NSCLC). One significant challenge in the effectiveness of this therapy is the potential development of resistance mechanisms, where autophagy up-regulation has been proposed as a key contributing factor. However, there is a lack of reliable biomarkers to predict outcomes on these patients. Interestingly, for addressing this gap, extracellular vesicles (EVs) and circulating tumor cells (CTCs) have emerged as potential sources of such biomarkers. In this study, we investigated EV-associated miRNAs and presence of autophagic CTCs in prospectively collected serial samples from 38 …

Dissociable Effects Of Alzheimer's Disease-Related Cognitive Dysfunction And Aging On Functional Brain Network Segregation, Ziwei Zhang, Micaela Y Chan, Liang Han, Claudia A Carreno, Ezra Winter-Nelson, Gagan S Wig

Faculty, Staff and Student Publications

Alzheimer's disease (AD) is associated with changes in large-scale functional brain network organization. Individuals with AD exhibit less segregated resting-state brain networks compared with individuals without dementia. However, declines in brain network segregation are also evident as adult individuals grow older. Determining whether these observations reflect unique or overlapping alterations on the functional connectome of the brain is essential for understanding the impact of AD on network organization and incorporating measures of functional brain network organization toward AD characterization. Relationships between AD dementia severity and participant's age on resting-state brain system segregation were examined in 326 cognitively healthy and 275 …

Circulating Tumor Dna Monitoring On Chemo-Immunotherapy For Risk Stratification In Advanced Non-Small Cell Lung Cancer, Bruna Pellini, Russell W Madison, Merrida A Childress, Shoshana T Miller, Ole Gjoerup, Jason Cheng, Richard S P Huang, Michael Krainock, Pratyush Gupta, Wei Zou, David S Shames, Solomon Moshkevich, Marcus Ballinger, Minetta C Liu, Amanda Young, Minu K Srivastava, Geoffrey R Oxnard, Mark A Socinski

Faculty, Staff and Student Publications

PURPOSE: Chemoimmunotherapy (chemoIO) is a prevalent first-line treatment for advanced driver-negative non-small cell lung cancer (NSCLC), with maintenance therapy given after induction. However, there is significant clinical variability in the duration, dosing, and timing of maintenance therapy after induction chemoIO. We used circulating tumor DNA (ctDNA) monitoring to inform outcomes in patients with advanced NSCLC receiving chemoIO.

EXPERIMENTAL DESIGN: This retrospective study included 221 patients from a phase III trial of atezolizumab+carboplatin+nab-paclitaxel versus carboplatin+nab-paclitaxel in squamous NSCLC (IMpower131). ctDNA monitoring used the FoundationOne Tracker involving comprehensive genomic profiling of pretreatment tumor tissue, variant selection using an algorithm to exclude nontumor …

Novel Clinical Trial Designs With Dose Optimization To Improve Long-Term Outcomes, Peter F Thall, Yong Zang, Andrew G Chapple, Ying Yuan, Ruitao Lin, David Marin, Pavlos Msaouel

Faculty, Staff and Student Publications

Conventional designs for choosing a dose for a new therapy may select doses that are unsafe or ineffective and fail to optimize progression-free survival time, overall survival time, or response/remission duration. We explain and illustrate limitations of conventional dose-finding designs and make four recommendations to address these problems. When feasible, a dose-finding design should account for long-term outcomes, include screening rules that drop unsafe or ineffective doses, enroll an adequate sample size, and randomize patients among doses. As illustrations, we review three designs that include one or more of these features. The first illustration is a trial that randomized patients …

Phase 1 Study Of Vibecotamab Identifies An Optimized Dose For Treatment Of Relapsed/Refractory Acute Myeloid Leukemia, Farhad Ravandi, Asad Bashey, James Foran, Wendy Stock, Raya Mawad, Nicholas Short, Musa Yilmaz, Hagop Kantarjian, Olatoyosi Odenike, Anand Patel, Raman Garcha, William Barrett Ainsworth, Raphael Clynes, Jitendra Kanodia, Ying Ding, Huajiang Li, Steve Kye, Alice Mims

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML), an aggressive malignancy with unmet medical need, lacks immunotherapeutic options. CD123, the cellular receptor for interleukin-3, expressed in AML is an attractive target for tumor-specific therapy. Vibecotamab (XmAb14045), a humanized bispecific antibody, monovalently binds both CD3 and CD123 to recruit cytotoxic T cells to kill CD123+ tumor cells. This phase 1 study's primary objectives were safety and tolerability and identification of a maximum tolerated dose/recommended dose for use as monotherapy in patients with relapsed/refractory AML. Identification of a recommended phase 2 vibecotamab dose comprised 3 step-up doses (Week 1), which were noted to reduce cytokine response …

Dhodh: A Promising Target In The Treatment Of T-Cell Acute Lymphoblastic Leukemia, Amy N Sexauer, Gabriela Alexe, Karin Gustafsson, Elizabeth Zanetakos, Jelena Milosevic, Mary Ayres, Varsha Gandhi, Yana Pikman, Kimberly Stegmaier, David B Sykes

Faculty, Staff and Student Publications

Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) have a poor prognosis with few therapeutic options. With the goal of identifying novel therapeutic targets, we used data from the Dependency Map project to identify dihydroorotate dehydrogenase (DHODH) as one of the top metabolic dependencies in T-ALL. DHODH catalyzes the fourth step of de novo pyrimidine nucleotide synthesis. Small molecule inhibition of DHODH rapidly leads to the depletion of intracellular pyrimidine pools and forces cells to rely on extracellular salvage. In the absence of sufficient salvage, this intracellular nucleotide starvation results in the inhibition of DNA and RNA synthesis, …

Pharyngeal Oxygen Delivery Device Sustains Manikin Lung Oxygenation Longer Than High-Flow Nasal Cannula, Jeramie B Hanson, John R Williams, Emily H Garmon, Phillip M Morris, Russell K Mcallister, Courtney N Shaver, William C Culp

Faculty, Staff and Student Publications

PURPOSE: Hypoxemia during a failed airway scenario is life threatening. A dual-lumen pharyngeal oxygen delivery device (PODD) was developed to fit inside a traditional oropharyngeal airway for undisrupted supraglottic oxygenation and gas analysis during laryngoscopy and intubation. We hypothesized that the PODD would provide oxygen as effectively as high-flow nasal cannula (HFNC) while using lower oxygen flow rates.

METHODS: We compared oxygen delivery of the PODD to HFNC in a preoxygenated, apneic manikin lung that approximated an adult functional residual capacity. Four arms were studied: HFNC at 20 and 60 liters per minute (LPM) oxygen, PODD at 10 LPM oxygen, …

The Landscape Of Alterations From 1407 Ultra-Rare Sarcomas From The Aacr Genie Database: Clinical Implications, Ryan A Denu, Justin T Moyers, Mohamed A Gouda, Anthony P Conley, Alexander J Lazar, Vivek Subbiah

Faculty, Staff and Student Publications

Purpose: Ultra-rare sarcomas (URS) comprise a group of orphan diseases with an incidence of ≤1/1,000,000 people per year. We aimed to assess clinically actionable genomic alterations in URS.

Experimental design: Data were extracted from the GENIE database using cBioPortal. OncoKB was used to assess for clinical actionability of mutations. Tumor mutational burden (TMB) was inferred from clinical sequencing data.

Results: Soft tissue (ST) URS made up 23.5% of ST sarcoma cases, and bone URS made up 16.5% of bone sarcoma cases. The most commonly mutated gene in all four groups was TP53. The most common fusions involved EWSR1. The most …

A Phase 1 Study Of Prophylactic Anakinra To Mitigate Icans In Patients With Large B-Cell Lymphoma, Paolo Strati, Andrew Jallouk, Qing Deng, Xubin Li, Lei Feng, Ryan Sun, Sherry Adkins, Swapna Johncy, Taylor Cain, Raphael E Steiner, Sairah Ahmed, Dai Chihara, Luis E Fayad, Swaminathan P Iyer, Sandra Horowitz, Loretta J Nastoupil, Ranjit Nair, Ahmed Hassan, Taher E Daoud, Misha Hawkins, Maria A Rodriguez, Elizabeth J Shpall, Jeremy L Ramdial, Partow Kebriaei, David S Hong, Jason R Westin, Sattva S Neelapu, Michael R Green

Faculty, Staff and Student Publications

No abstract provided.

Gasdermin D Permeabilization Of Mitochondrial Inner And Outer Membranes Accelerates And Enhances Pyroptosis, Rui Miao, Cong Jiang, Winston Y Chang, Haiwei Zhang, Jinsu An, Felicia Ho, Pengcheng Chen, Han Zhang, Caroline Junqueira, Dulguun Amgalan, Felix G Liang, Junbing Zhang, Charles L Evavold, Iva Hafner-Bratkovič, Zhibin Zhang, Pietro Fontana, Shiyu Xia, Markus Waldeck-Weiermair, Youdong Pan, Thomas Michel, Liron Bar-Peled, Hao Wu, Jonathan C Kagan, Richard N Kitsis, Peng Zhang, Xing Liu, Judy Lieberman

Faculty, Staff and Student Publications

Gasdermin D (GSDMD)-activated inflammatory cell death (pyroptosis) causes mitochondrial damage, but its underlying mechanism and functional consequences are largely unknown. Here, we show that the N-terminal pore-forming GSDMD fragment (GSDMD-NT) rapidly damaged both inner and outer mitochondrial membranes (OMMs) leading to reduced mitochondrial numbers, mitophagy, ROS, loss of transmembrane potential, attenuated oxidative phosphorylation (OXPHOS), and release of mitochondrial proteins and DNA from the matrix and intermembrane space. Mitochondrial damage occurred as soon as GSDMD was cleaved prior to plasma membrane damage. Mitochondrial damage was independent of the B-cell lymphoma 2 family and depended on GSDMD-NT binding to cardiolipin. Canonical and …

Cigarette Smoke Exposure Accelerates Aml Progression In Flt3-Itd Models, Mary Figueroa, Huaxian Ma, Mansour Alfayez, Daniel Enrique Morales-Mantilla, Fei Wang, Yue Lu, Marcos R Estecio, Katherine Y King, Eugenie Kleinerman, Seyed Javad Moghaddam, Naval Daver, Michael Andreeff, Marina Konopleva, Courtney Dinardo, Joya Chandra

Faculty, Staff and Student Publications

No abstract provided.